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Consulenza farmacologica per eritromicina, alfentanile e voriconazolo

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Version 6.0.32 (Beta Preview)

Sommario Sommario info 42%

Farmacocinetica -33%
Eritromicina
Alfentanile
Voriconazolo
Punteggi -12%
Estensione di tempo QT
Effetti anticolinergici
Effetti serotoninergici
Effetti avversi del farmaco -13%
Nausea
Visione offuscata
Vomito

Varianti ✨

Per la valutazione computazionalmente intensiva delle varianti, scegli l'abbonamento standard a pagamento.

farmaco Aree di applicazione

Spiegazioni per i pazienti

undefined Farmacocinetica info -33%

∑ Esposizioneaerialfvor
Eritromicina 1.1 n.a. 1.1
Alfentanile 10.29 2.66 5.53
Voriconazolo 1.1 [0.83,4.49] 1 1.1 1
Genotipi rilevanti: 1CYP2C19
Simbolo (a): variazione x volte dell'AUC
Leggenda (n.a.): Informazioni non disponibili

I cambiamenti nell'esposizione menzionati si riferiscono ai cambiamenti nella curva concentrazione plasmatica-tempo [AUC]. L'esposizione alla alfentanile aumenta al 1029%, se combinato con eritromicina (266%) e voriconazolo (553%). Questo può portare a un aumento degli effetti collaterali. L'esposizione alla eritromicina aumenta al 110%, se combinato con voriconazolo (110%). Al momento non possiamo stimare l'influenza della alfentanile. L'esposizione alla voriconazolo aumenta al 110%, se combinato con eritromicina (110%) e alfentanile (100%). L'AUC è compresa tra 83% e 449% a seconda del CYP2C19.

Valutazione: I parametri farmacocinetici della popolazione media sono utilizzati come punto di partenza per il calcolo delle singole variazioni di esposizione dovute alle interazioni.
La eritromicina ha una bassa biodisponibilità orale [ F ] del 24%, motivo per cui il livello plasmatico massimo [Cmax] tende a cambiare fortemente con un'interazione. L'emivita terminale [ t12 ] è piuttosto breve a 2.3 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti rapidamente. Il legame proteico [ Pb ] è moderatamente forte al 73% e il volume di distribuzione [ Vd ] è di 56 litri, ecco perché, con una velocità di estrazione epatica media di 0,9, sono rilevanti sia il flusso sanguigno epatico [Q] che una variazione del legame proteico [Pb]. Il metabolismo avviene principalmente tramite CYP3A4 e il trasporto attivo avviene in parte tramite MRP2 e PGP.
La alfentanile ha una biodisponibilità orale media [ F ] del 41%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare con un'interazione. L'emivita terminale [ t12 ] è piuttosto breve a 1.1 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti rapidamente. Il legame proteico [ Pb ] è moderatamente forte al 90% e il volume di distribuzione [ Vd ] è di 36 litri nell'intervallo medio. Poiché la sostanza ha una bassa velocità di estrazione epatica di 0,9, lo spostamento dal legame proteico [Pb] nel contesto di un'interazione può aumentare l'esposizione. Il metabolismo avviene principalmente tramite CYP3A4.
La voriconazolo ha un'elevata biodisponibilità orale [ F ] del 88%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare poco durante un'interazione. L'emivita terminale [ t12 ] è piuttosto breve a 6 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti rapidamente. Il legame proteico [ Pb ] è piuttosto debole al 58% e il volume di distribuzione [ Vd ] è molto grande a 90 litri, Poiché la sostanza ha una bassa velocità di estrazione epatica di 0,9, lo spostamento dal legame proteico [Pb] nel contesto di un'interazione può aumentare l'esposizione. Il metabolismo avviene tramite CYP2C19, CYP2C9 e CYP3A4, tra gli altri.

trasmettitore Effetti serotoninergici info -4%

Punteggi ∑ Punti erialfvor
Effetti serotoninergici a 1 Ø + Ø
Simbolo (a): Rischio aumentato da 5 punti.

Raccomandazione: Come misura precauzionale, devono essere presi in considerazione i sintomi della sovrastimolazione serotoninergica, specialmente dopo aver aumentato la dose e alle dosi nell'intervallo terapeutico superiore.

Valutazione: La alfentanile ha un lieve effetto sul sistema serotoninergico. Il rischio di una sindrome serotoninergica può essere classificato basso con questo farmaco se il dosaggio rientra nell'intervallo abituale. Secondo le nostre conoscenze, né la eritromicina né la voriconazolo aumentano l'attività serotoninergica.

trasmettitore Effetti anticolinergici info -0%

Punteggi ∑ Punti erialfvor
Kiesel b 0ØØØ
Simbolo (b): Rischio aumentato da 3 punti.

Valutazione: Secondo i nostri risultati, né la eritromicina, alfentanile né la voriconazolo aumentano l'attività anticolinergica.

elettrocardiogramma Estensione di tempo QT info -9%

Punteggi ∑ Punti erialfvor
RISK-PATH c 3.25+++Ø+
Simbolo (c): Rischio aumentato da 10 punti. Occorre rispondere alle domande sui fattori di rischio.

Raccomandazione: Per poter stimare il rischio individuale di aritmie, si consiglia di rispondere in modo completo alle seguenti .

Valutazione: In combinazione, eritromicina e voriconazolo possono potenzialmente innescare aritmie ventricolari di tipo torsione di punta. Non conosciamo alcun potenziale di prolungamento dell'intervallo QT per la alfentanile.

Altri effetti collaterali Effetti collaterali generali info -13%

Effetti collaterali ∑ frequenza erialfvor
Nausea32.6 %+28.0↑5.4
Visione offuscata26.0 %n.a.n.a.26.0
Vomito22.4 %+18.0↑4.4
Ipertensione18.0 %n.a.18.0↑n.a.
Dolore addominale12.9 %+n.a.12.0
Tachicardia12.0 %n.a.12.0↑n.a.
Ipopotassiemia11.0 %n.a.n.a.11.0
Ipotensione10.0 %n.a.10.0↑n.a.
Trombocitopenia10.0 %n.a.n.a.10.0
Dispnea10.0 %n.a.n.a.10.0
Estratto tabellare degli effetti collaterali più comuni
Segno (+): effetto collaterale descritto, ma frequenza non nota
Segno (↑/↓): frequenza piuttosto maggiore / minore a causa dell'esposizione

Mentale
Allucinazioni (9.5%): voriconazolo

Dermatologico
Eruzione cutanea (7%): voriconazolo
Sindrome di Stevens Johnson (1.9%): eritromicina, voriconazolo
Necrolisi epidermica tossica (1.9%): eritromicina, voriconazolo
Eritema multiforme (1.9%): voriconazolo
Melanoma maligno (1.9%): voriconazolo
Carcinoma spinocellulare (1.9%): voriconazolo

Respiratorio
Apnea (6%): alfentanile
Depressione respiratoria (2%): alfentanile
Spasmo laringeo: alfentanile

Oftalmologico
Fotofobia (6%): voriconazolo
Neurite ottica: voriconazolo

Sistemico
Febbre (5.7%): voriconazolo

Hepatica
Epatite colestatica (4.9%): eritromicina, voriconazolo
Insufficienza epatica (1.9%): eritromicina, voriconazolo
Epatotossicità (1.9%): voriconazolo
Ittero (1.9%): voriconazolo
Iperbilirubinemia: voriconazolo

Neurologico
Mal di testa (3%): voriconazolo
Convulsioni: eritromicina, alfentanile
Aumento della pressione intracranica: alfentanile

Gastrointestinale
Diarrea (2.9%): eritromicina, voriconazolo
Perdita di appetito: eritromicina
Diarrea da Clostridium difficile: eritromicina
Pancreatite: eritromicina, voriconazolo

Cardiaco
Edema periferico (1.9%): voriconazolo
Aritmia ventricolare: eritromicina
Asistolia: alfentanile
Bradicardia: alfentanile

Immunologico
Reazione di ipersensibilità: alfentanile
Reazioni allergiche della pelle: eritromicina
Angioedema: eritromicina

Auricolare
Perdita dell'udito: eritromicina

Renale
Nefrite tubulointerstiziale: eritromicina
Insufficienza renale: voriconazolo

Limitazioni Limitazioni

Sulla base delle vostre e delle informazioni scientifiche, valutiamo il rischio individuale di effetti collaterali indesiderati. Le barre arancioni indicano il potenziale di base dei farmaci per causare questo effetto collaterale. Queste raccomandazioni hanno lo scopo di consigliare i professionisti e non sostituiscono la consultazione con un medico. Nella versione di prova ristretta (alfa), il rischio di tutte le sostanze non è stato ancora valutato in modo definitivo.

letteratura Riferimenti letterari

1. Wilson JT et al. Pharmacokinetics of Erythromycin in man. Antibiotics and chemotherapy. 1978
Authors: Wilson JT van Boxtel CJ
Abstract: No Abstract available
Pubmed Id: 27136
2. Kilani F et al. [Attack of torsades de pointes induced by an intravenous injection of erythromycin lactobionate]. Annales francaises d'anesthesie et de reanimation. 1988
Authors: Kilani F Marsepoil T
Abstract: No Abstract available
Pubmed Id: 3408043
3. Freedman RA et al. Effect of erythromycin on ventricular arrhythmias and ventricular repolarization in idiopathic long QT syndrome. The American journal of cardiology. 1987
Authors: Freedman RA Anderson KP Green LS Mason JW
Abstract: No Abstract available
Pubmed Id: 3812231
4. Wong CB et al. Erythromycin induced torsades de pointes. The Nebraska medical journal. 1995
Authors: Wong CB Windle J
Abstract: Erythromycin is a widely used antibiotic in today's armamentarium of antibiotics. Although erythromycin induced ventricular tachyarrhythmia is rare, this potentially life-threatening reaction should be kept in mind. The relative rarity of 'torsades de pointes' arrhythmia suggests that other predisposing factors contribute to the acquired long QT syndrome. Since more and more macrolide products have been approved by the Food and Drug Administration for use in the United States, the potential problem with 'torsades de pointes' may exist with each of the macrolide antibiotic. Until the exact mechanisms of the arrhythmia are worked out, close monitoring of rhythms and QT intervals of high risk patients who require erythromycin is certainly advisable. Only a heightened awareness among the physicians and medical personnel can the adverse outcome be minimized.
Pubmed Id: 7566254
5. Somogyi AA et al. Evaluation of the intestinal absorption of erythromycin in man: absolute bioavailability and comparison with enteric coated erythromycin. Pharmaceutical research. 1995
Authors: Somogyi AA Bochner F Hetzel D Williams DB
Abstract: To determine the role of acid hydrolysis on the gastrointestinal absorption of erythromycin, six healthy subjects received erythromycin as a 240 mg intravenous dose, a 250 mg oral solution administered via endoscope directly into the duodenum and bypassing the stomach, and an enteric-coated 250 mg capsule. Blood samples were collected for 6 hours and serum erythromycin quantified by a microbiological method. The time to achieve maximum serum concentrations for the solution was 0.25 +/- 0.08 (mean +/- SD) hours and for the capsule was 2.92 +/- 0.55 hours. The absolute bioavailability of erythromycin from the capsule was 32 +/- 7% and for the duodenal solution 43 +/- 14%. The ratio of the areas under the serum erythromycin concentration-time curve of capsule to solution was 80 +/- 28% (range 38 to 110%). There is substantial loss of erythromycin apart from gastric acid hydrolysis, which cannot be accounted for by hepatic first-pass metabolism. Attempts to further improve the oral bioavailability of erythromycin beyond 50% by manipulation of formulation are likely to be futile.
Pubmed Id: 7724478
6. Johnston A The pharmacokinetics of voriconazole. British journal of clinical pharmacology. 2003
Authors: Johnston A
Abstract: No Abstract available
Pubmed Id: 14616406
7. Klees TM et al. Metabolism of alfentanil by cytochrome p4503a (cyp3a) enzymes. Drug metabolism and disposition: the biological fate of chemicals. 2005
Authors: Klees TM Sheffels P Dale O Kharasch ED
Abstract: The synthetic opioid alfentanil is an analgesic and an in vivo probe for hepatic and first-pass CYP3A activity. Alfentanil is a particularly useful CYP3A probe because pupil diameter change is a surrogate for plasma concentrations, thereby affording noninvasive assessment of CYP3A. Alfentanil undergoes extensive CYP3A4 metabolism via two major pathways, forming noralfentanil and N-phenylpropionamide. This investigation evaluated alfentanil metabolism in vitro to noralfentanil and N-phenylpropionamide, by expressed CYP3A5 and CYP3A7 in addition to CYP3A4, with and without coexpressed or exogenous cytochrome b(5). Effects of the CYP3A inhibitors troleandomycin and ketoconazole were also determined. Rates of noralfentanil and N-phenylpropionamide formation by CYP3A4 and 3A5 in the absence of b(5) were generally equivalent, although the metabolite formation ratio differed, whereas those by CYP3A7 were substantially less. CYP3A4 and 3A5 were equipotently inhibited by troleandomycin, whereas ketoconazole was an order of magnitude more potent toward CYP3A4. Cytochrome b(5) qualitatively and quantitatively altered alfentanil metabolism, with b(5) coexpression having a greater effect than exogenous addition. Addition or coexpression of b(5) markedly stimulated the formation of both metabolites and changed the formation of noralfentanil but not N-phenylpropionamide from apparent single-site to multisite Michaelis-Menten kinetics. These results demonstrate that alfentanil is a substrate for CYP3A5 in addition to CYP3A4, and the effects of the CYP3A inhibitors troleandomycin and ketoconazole are CYP3A enzyme-selective. Alfentanil is one of the few CYP3A substrates that is metabolized in vitro as avidly by both CYP3A4 and 3A5. Polymorphic CYP3A5 expression may contribute to inter-individual variability in alfentanil metabolism.
Pubmed Id: 15557344
8. Kharasch ED et al. Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimally invasive and noninvasive probes for hepatic and first-pass CYP3A activity. Journal of clinical pharmacology. 2005
Authors: Kharasch ED Walker A Hoffer C Sheffels P
Abstract: This investigation determined the ability of alfentanil miosis and single-point concentrations to detect various degrees of CYP3A inhibition. Results were compared with those for midazolam, an alternative CYP3A probe. Twelve volunteers were studied in a randomized 4-way crossover, targeting 12%, 25%, and 50% inhibition of hepatic CYP3A. They received 0, 100, 200, or 400 mg oral fluconazole, followed 1 hour later by 1 mg intravenous midazolam and then 15 microg/kg intravenous alfentanil 1 hour later. The next day, they received fluconazole, followed by 3 mg oral midazolam and 40 microg/kg oral alfentanil. Dark-adapted pupil diameters were measured coincident with blood sampling. Area under the plasma concentration-time curve (AUC) ratios (fluconazole/control) after 100, 200, and 400 mg fluconazole were (geometric mean) 1.3*, 1.4*, and 2.0* for intravenous midazolam and 1.2*, 1.6*, and 2.2* for intravenous alfentanil (*significantly different from control), indicating 16% to 21%, 31% to 36%, and 43% to 53% inhibition of hepatic CYP3A. Single-point concentration ratios were 1.5*, 1.8*, and 2.4* for intravenous midazolam (at 5 hours) and 1.2*, 1.6*, and 2.2* for intravenous alfentanil (at 4 hours). Pupil miosis AUC ratios were 0.9, 1.0, and 1.2*. After oral dosing, plasma AUC ratios were 2.3*, 3.6*, and 5.3* for midazolam and 1.8*, 2.9*, and 4.9* for alfentanil; plasma single-point ratios were 2.4*, 4.5*, and 6.9* for midazolam and 1.8*, 2.9*, and 4.9* for alfentanil, and alfentanil miosis ratios were 1.1, 1.9*, and 2.7*. Plasma concentration AUC ratios of alfentanil and midazolam were equivalent for detecting hepatic and first-pass CYP3A inhibition. Single-point concentrations were an acceptable surrogate for formal AUC determinations and as sensitive as AUCs for detecting CYP3A inhibition. Alfentanil miosis could detect 50% to 70% inhibition of CYP3A activity, but was less sensitive than plasma AUCs. Further refinements are needed to increase the sensitivity of alfentanil miosis for detecting small CYP3A changes.
Pubmed Id: 16172184
9. Levêque D et al. Clinical pharmacokinetics of voriconazole. International journal of antimicrobial agents. 2006
Authors: Levêque D Nivoix Y Jehl F Herbrecht R
Abstract: This review presents the published clinical pharmacokinetic data for the antifungal agent voriconazole. Aspects regarding absorption, tissue distribution, elimination and kinetic interactions are also discussed.
Pubmed Id: 16563707
10. Theuretzbacher U et al. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clinical pharmacokinetics. 2006
Authors: Theuretzbacher U Ihle F Derendorf H
Abstract: Voriconazole is the first available second-generation triazole with potent activity against a broad spectrum of clinically significant fungal pathogens, including Aspergillus,Candida, Cryptococcus neoformans, and some less common moulds. Voriconazole is rapidly absorbed within 2 hours after oral administration and the oral bioavailability is over 90%, thus allowing switching between oral and intravenous formulations when clinically appropriate. Voriconazole shows nonlinear pharmacokinetics due to its capacity-limited elimination, and its pharmacokinetics are therefore dependent upon the administered dose. With increasing dose, voriconazole shows a superproportional increase in area under the plasma concentration-time curve (AUC). In doses used in children (age < 12 years) voriconazole pharmacokinetics appear to be linear. Steady-state plasma concentrations are reached approximately 5 days after both intravenous and oral administration; however, steady state is reached within 24 hours with voriconazole administered as an intravenous loading dose. The volume of distribution of voriconazole is 2-4.6 L/kg, suggesting extensive distribution into extracellular and intracellular compartments. Voriconazole was measured in tissue samples of brain, liver, kidney, heart, lung as well as cerebrospinal fluid. The plasma protein binding is about 60% and independent of dose or plasma concentrations. Clearance is hepatic via N-oxidation by the hepatic cytochrome P450 (CYP) isoenzymes, CYP2C19, CYP2C9 and CYP3A4. The elimination half-life of voriconazole is approximately 6 hours, and approximately 80% of the total dose is recovered in the urine, almost completely as metabolites. As with other azole drugs, the potential for drug interactions is considerable. Voriconazole shows time-dependent fungistatic activity against Candida species and time-dependent slow fungicidal activity against Aspergillus species. A short post-antifungal effect of voriconazole is evident only for Aspergillus species. The predictive pharmacokinetic/pharmacodynamic parameter for voriconazole treatment efficacy in Candida infections is the free drug AUC from 0 to 24 hour : minimum inhibitory concentration ratio.
Pubmed Id: 16802848
11. Saari TI et al. Voriconazole, but not terbinafine, markedly reduces alfentanil clearance and prolongs its half-life. Clinical pharmacology and therapeutics. 2006
Authors: Saari TI Laine K Leino K Valtonen M Neuvonen PJ Olkkola KT
Abstract: OBJECTIVE: Alfentanil is a short-acting synthetic opioid analgesic, which is extensively metabolized, mainly by hepatic cytochrome P450 (CYP) 3A enzymes. Concomitant administration of alfentanil and CYP3A inhibitors may lead to clinically important drug interactions. We investigated the possible interactions between alfentanil and orally administered voriconazole and terbinafine. METHODS: A randomized crossover study design in 3 phases was used. Twelve healthy volunteers were given 20 microg/kg intravenous alfentanil without pretreatment (control), after oral voriconazole administration (400 mg twice on the first day and 200 mg twice on the second day), or after oral terbinafine administration (250 mg once daily for 3 days). Plasma concentrations of alfentanil were measured for 10 hours, and the pharmacokinetic parameters were calculated by use of noncompartmental methods. RESULTS: Voriconazole decreased the mean plasma clearance of intravenous alfentanil by 85%, from the control value of 4.4+/-2.4 mL.min-1.kg-1 to 0.67+/-0.27 mL.min-1.kg-1 (P<.001), and prolonged its elimination half-life from 1.5+/-0.49 hours to 6.6+/-1.8 hours (P<.001). The area under the alfentanil plasma concentration-time curve was increased by 6-fold by voriconazole (P<.001). Terbinafine had no statistically significant effect on the pharmacokinetics of alfentanil. Alfentanil administration caused nausea in 5 volunteers and vomiting in 2. These side effects all occurred in volunteers in the voriconazole phase. CONCLUSION: Oral voriconazole, but not terbinafine, markedly inhibited the metabolism of alfentanil. Caution should be exercised when alfentanil is given to patients receiving voriconazole. It is reasonable to assume that patients receiving voriconazole require 70% to 90% less alfentanil for the maintenance of analgesia than patients who are not receiving concomitant CYP3A inhibitors.
Pubmed Id: 17112806
12. Philips JA et al. Torsades de pointes associated with voriconazole use. Transplant infectious disease : an official journal of the Transplantation Society. 2007
Authors: Philips JA Marty FM Stone RM Koplan BA Katz JT Baden LR
Abstract: We describe 2 patients who developed prolonged QTc interval on electrocardiogram while being treated with voriconazole. The first patient had undergone induction chemotherapy for acute myelogenous leukemia, and her course had been complicated by invasive aspergillosis and an acute cardiomyopathy. She developed torsades de pointes 3 weeks after starting voriconazole therapy. She was re-challenged with voriconazole without recurrent QTc prolongation or cardiac dysfunction. The second patient had a significantly prolonged QTc interval while on voriconazole therapy. We recommend careful monitoring for QTc prolongation and arrhythmia in patients who are receiving voriconazole, particularly those who have significant electrolyte disturbances, are on concomitant QT prolonging medications, have heart failure such as from a dilated cardiomyopathy, or have recently received anthracycline-based chemotherapy. The potential for synergistic cardiotoxicity must be carefully considered.
Pubmed Id: 17313469
13. Kharasch ED et al. Influence of CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of the cytochrome P4503A probes alfentanil and midazolam. Clinical pharmacology and therapeutics. 2007
Authors: Kharasch ED Walker A Isoherranen N Hoffer C Sheffels P Thummel K Whittington D Ensign D
Abstract: The hepatic and first-pass cytochrome P4503A (CYP3A) probe alfentanil (ALF) is also metabolized in vitro by CYP3A5. Human hepatic microsomal ALF metabolism is higher in livers with at least one CYP3A5*1 allele and higher CYP3A5 protein content, compared with CYP3A5*3 homozygotes with little CYP3A5. The influence of CYP3A5 genotype on ALF pharmacokinetics and pharmacodynamics was studied, and compared to midazolam (MDZ), another CYP3A probe. Healthy volunteers (58 men, 41 women) were genotyped for CYP3A5 *1, *3, *6, and *7 alleles. They received intravenous MDZ then ALF, and oral MDZ and ALF the next day. Plasma MDZ and ALF concentrations were determined by mass spectrometry. Dark-adapted pupil diameters were determined coincident with blood sampling. In CYP3A5(*)3/(*)3 (n=62), (*)1/(*)3 (n=28), and (*)1/(*)1 (n=8) genotypes, systemic clearances of ALF were 4.6+/-1.8, 4.8+/-1.7, and 3.9+/-1.7 ml/kg/min and those of MDZ were 7.8+/-2.3, 7.7+/-2.3, and 6.0+/-1.4 ml/kg/min, respectively (not significant), and apparent oral clearances were 11.8+/-7.2, 13.3+/-6.1, and 12.6+/-8.2 ml/kg/min for ALF and 35.2+/-19.0, 36.4+/-15.7, and 29.4+/-9.3 ml/kg/min for MDZ (not significant). Clearances were not different between African Americans (n=25) and Whites (n=68), or between CYP3A5 genotypes within African Americans. ALF pharmacodynamics was not different between CYP3A5 genotypes. There was consistent concordance between ALF and MDZ, in clearances and extraction ratios. Thus, in a relatively large cohort of healthy subjects with constitutive CYP3A activity, CYP3A5 genotype had no effect on the systemic or apparent oral clearances, or pharmacodynamics, of the CYP3A probes ALF and MDZ, despite affecting their hepatic microsomal metabolism.
Pubmed Id: 17554244
14. Murtagh FE et al. The use of opioid analgesia in end-stage renal disease patients managed without dialysis: recommendations for practice. Journal of pain & palliative care pharmacotherapy. 2007
Authors: Murtagh FE Chai MO Donohoe P Edmonds PM Higginson IJ
Abstract: The numbers of patients dying with end-stage renal disease (ESRD), particularly those managed conservatively (without dialysis) or withdrawing from dialysis is increasing rapidly in developed countries. There is growing awareness of the extensive symptom control needs of these patients. Pain is a common problem, and has been both under-recognized and under-treated. It is challenging to manage, largely because of the constraints very poor renal function places on use of medication. Although pharmacological reviews of opioid use in renal failure have been published, there is a need for clinical recommendations to aid palliative and renal specialists in providing effective pain control. This review describes the pharmacological evidence for and against the use of the different opioid medications, and translates this into clinical recommendations for ESRD patients managed conservatively, not for those on dialysis for whom there are different pharmacological considerations. Acetaminophen (paracetamol) is recommended at Step 1 of the World Health Organization ladder. Of the Step 2 analgesics, tramadol is the least problematic, although dose reduction and increased dosing interval are required, and caution should be exercised. Of the Step 3 analgesics, fentanyl, alfentanil and methadone are recommended. There is limited evidence for buprenorphine, although theoretical reasons why it may be a good choice for these patients. Hydromorphone and oxycodone cannot be recommended because of extremely limited evidence, although each is likely a better choice than morphine or diamorphine. Morphine and diamorphine themselves are not recommended because of known accumulation of potentially toxic metabolites.
Pubmed Id: 17844723
15. Kharasch ED et al. Methadone pharmacokinetics are independent of cytochrome P4503A (CYP3A) activity and gastrointestinal drug transport: insights from methadone interactions with ritonavir/indinavir. Anesthesiology. 2009
Authors: Kharasch ED Hoffer C Whittington D Walker A Bedynek PS
Abstract: BACKGROUND: Methadone clearance is highly variable, and drug interactions are problematic. Both have been attributed to CYP3A, but actual mechanisms are unknown. Drug interactions can provide such mechanistic information. Ritonavir/indinavir, one of the earliest protease inhibitor combinations, may inhibit CYP3A. We assessed ritonavir/indinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A activity, and intestinal transporters (P-glycoprotein) activity. CYP3A and transporters were assessed with alfentanil and fexofenadine, respectively. METHODS: Twelve healthy human immunodeficiency virus-negative volunteers underwent a sequential three-part crossover. On three consecutive days, they received oral alfentanil/fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone, repeated after acute (3 days) and steady-state (2 weeks) ritonavir/indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were assessed by miosis. RESULTS: Alfentanil apparent oral clearance was inhibited more than 97% by both acute and steady-state ritonavir/indinavir, and systemic clearance was inhibited more than 90% due to diminished hepatic and intestinal extraction. Ritonavir/indinavir increased fexofenadine area under the plasma concentration-time curve four- to five-fold, suggesting significant inhibition of gastrointestinal P-glycoprotein. Ritonavir/indinavir slightly increased methadone N-demethylation, but it had no significant effects on methadone plasma concentrations or on systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Ritonavir/indinavir had no significant effects on methadone plasma concentration-effect relationships. CONCLUSIONS: Inhibition of both hepatic and intestinal CYP3A activity is responsible for ritonavir/indinavir drug interactions. Methadone disposition was unchanged, despite profound inhibition of CYP3A activity, suggesting little or no role for CYP3A in clinical methadone metabolism and clearance. Methadone bioavailability was unchanged, despite inhibition of gastrointestinal P-glycoprotein activity, suggesting that this transporter does not limit methadone intestinal absorption.
Pubmed Id: 19225389
16. Kharasch ED et al. Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity. Drug and alcohol dependence. 2009
Authors: Kharasch ED Walker A Whittington D Hoffer C Bedynek PS
Abstract: BACKGROUND: Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively. METHODS: Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis). RESULTS: Nelfinavir decreased intravenous and oral methadone plasma concentrations 40-50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone; apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (S>R) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50 and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration-effect (miosis) curve leftward and upward. CONCLUSIONS: Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects.
Pubmed Id: 19232844
17. Johnson HJ et al. Voriconazole pharmacokinetics in liver transplant recipients. Antimicrobial agents and chemotherapy. 2010
Authors: Johnson HJ Han K Capitano B Blisard D Husain S Linden PK Marcos A Kwak EJ Potoski B Paterson DL Romkes M Venkataramanan R
Abstract: The objective of this study was to evaluate the pharmacokinetics of voriconazole and the potential correlations between pharmacokinetic parameters and patient variables in liver transplant patients on a fixed-dose prophylactic regimen. Multiple blood samples were collected within one dosing interval from 15 patients who were initiated on a prophylactic regimen of voriconazole at 200 mg enterally (tablets) twice daily starting immediately posttransplant. Voriconazole plasma concentrations were measured using high-pressure liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis was performed to estimate pharmacokinetic parameters. The mean apparent systemic clearance over bioavailability (CL/F), apparent steady-state volume of distribution over bioavailability (Vss/F), and half-life (t1/2) were 5.8+/-5.5 liters/h, 94.5+/-54.9 liters, and 15.7+/-7.0 h, respectively. There was a good correlation between the area under the concentration-time curve from 0 h to infinity (AUC0-infinity) and trough voriconazole plasma concentrations. t1/2, maximum drug concentration in plasma (Cmax), trough level, AUC0-infinity, area under the first moment of the concentration-time curve from 0 h to infinity (AUMC0-infinity), and mean residence time from 0 h to infinity (MRT0-infinity) were significantly correlated with postoperative time. t1/2, lambda, AUC0-infinity, and CL/F were significantly correlated with indices of liver function (aspartate transaminase [AST], total bilirubin, and international normalized ratio [INR]). The Cmax, last concentration in plasma at 12 h (Clast), AUMC0-infinity, and MRT0-infinity were significantly lower in the presence of deficient CYP2C19*2 alleles. Donor characteristics had no significant correlation with any of the pharmacokinetic parameters estimated. A fixed dosing regimen of voriconazole results in a highly variable exposure of voriconazole in liver transplant patients. Given that trough voriconazole concentration is a good measure of drug exposure (AUC), the voriconazole dose can be individualized based on trough concentration measurements in liver transplant patients.
Pubmed Id: 19933807
18. Sun H et al. Hepatic clearance, but not gut availability, of erythromycin is altered in patients with end-stage renal disease. Clinical pharmacology and therapeutics. 2010
Authors: Sun H Frassetto LA Huang Y Benet LZ
Abstract: Nonrenal clearance of drugs can be significantly lower in patients with end-stage renal disease (ESRD) than in those with normal renal function. Using erythromycin (ER) as a probe compound, we investigated whether this decrease in nonrenal clearance is due to reduced hepatic clearance (CL(H)) and/or gut metabolism. We also examined the potential effects of the uremic toxins 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate (Indox) on ER disposition. Route-randomized, two-way crossover pharmacokinetic studies of ER were conducted in 12 ESRD patients and 12 healthy controls after oral (250 mg) and intravenous (125 mg) dosing with ER. In patients with ESRD, CL(H) decreased 31% relative to baseline values (0.35 +/- 0.14 l/h/kg vs. 0.51 +/- 0.13 l/h/kg, P = 0.01), with no change in steady-state volume of distribution. With oral dosing, the bioavailability of ER increased 36% in patients with ESRD, and this increase was not related to changes in gut availability. As expected, plasma levels of CMPF and Indox were significantly higher in the patients than in the healthy controls. However, no correlation was observed between CL(H) of ER and the levels of uremic toxins.
Pubmed Id: 20090676
19. Franke RM et al. Effect of ABCC2 (MRP2) transport function on erythromycin metabolism. Clinical pharmacology and therapeutics. 2011
Authors: Franke RM Lancaster CS Peer CJ Gibson AA Kosloske AM Orwick SJ Mathijssen RH Figg WD Baker SD Sparreboom A
Abstract: The macrolide antiobiotic erythromycin undergoes extensive hepatic metabolism and is commonly used as a probe for cytochrome P450 (CYP) 3A4 activity. By means of a transporter screen, erythromycin was identified as a substrate for the transporter ABCC2 (MRP2) and its murine ortholog, Abcc2. Because these proteins are highly expressed on the biliary surface of hepatocytes, we hypothesized that impaired Abcc2 function may influence the rate of hepatobiliary excretion and thereby enhance erythromycin metabolism. Using Abcc2 knockout mice, we found that Abcc2 deficiency was associated with a significant increase in erythromycin metabolism, whereas murine Cyp3a protein expression and microsomal Cyp3a activity were not affected. Next, in a cohort of 108 human subjects, we observed that homozygosity for a common reduced-function variant in ABCC2 (rs717620) was also linked to an increase in erythromycin metabolism but was not correlated with the clearance of midazolam. These results suggest that impaired ABCC2 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.
Pubmed Id: 21451505
20. King S et al. A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: a European Palliative Care Research Collaborative opioid guidelines project. Palliative medicine. 2011
Authors: King S Forbes K Hanks GW Ferro CJ Chambers EJ
Abstract: BACKGROUND: Opioid use in patients with renal impairment can lead to increased adverse effects. Opioids differ in their effect in renal impairment in both efficacy and tolerability. This systematic literature review forms the basis of guidelines for opioid use in renal impairment and cancer pain as part of the European Palliative Care Research Collaborative's opioid guidelines project. OBJECTIVE: The objective of this study was to identify and assess the quality of evidence for the safe and effective use of opioids for the relief of cancer pain in patients with renal impairment and to produce guidelines. SEARCH STRATEGY: The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MedLine, EMBASE and CINAHL were systematically searched in addition to hand searching of relevant journals. SELECTION CRITERIA: Studies were included if they reported a clinical outcome relevant to the use of selected opioids in cancer-related pain and renal impairment. The selected opioids were morphine, diamorphine, codeine, dextropropoxyphene, dihydrocodeine, oxycodone, hydromorphone, buprenorphine, tramadol, alfentanil, fentanyl, sufentanil, remifentanil, pethidine and methadone. No direct comparator was required for inclusion. Studies assessing the long-term efficacy of opioids during dialysis were excluded. DATA COLLECTION AND ANALYSIS: This is a narrative systematic review and no meta-analysis was performed. The Grading of RECOMMENDATIONS Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of the studies and to formulate guidelines. MAIN RESULTS: Fifteen original articles were identified. Eight prospective and seven retrospective clinical studies were identified but no randomized controlled trials. No results were found for diamorphine, codeine, dihydrocodeine, buprenorphine, tramadol, dextropropoxyphene, methadone or remifentanil. CONCLUSIONS: All of the studies identified have a significant risk of bias inherent in the study methodology and there is additional significant risk of publication bias. Overall evidence is of very low quality. The direct clinical evidence in cancer-related pain and renal impairment is insufficient to allow formulation of guidelines but is suggestive of significant differences in risk between opioids. RECOMMENDATIONS: RECOMMENDATIONS regarding opioid use in renal impairment and cancer pain are made on the basis of pharmacokinetic data, extrapolation from non-cancer pain studies and from clinical experience. The risk of opioid use in renal impairment is stratified according to the activity of opioid metabolites, potential for accumulation and reports of successful or harmful use. Fentanyl, alfentanil and methadone are identified, with caveats, as the least likely to cause harm when used appropriately. Morphine may be associated with toxicity in patients with renal impairment. Unwanted side effects with morphine may be satisfactorily dealt with by either increasing the dosing interval or reducing the 24 hour dose or by switching to an alternative opioid.
Pubmed Id: 21708859
21. Aypar E et al. Voriconazole-induced QT interval prolongation and torsades de pointes. Pediatrics international : official journal of the Japan Pediatric Society. 2011
Authors: Aypar E Kendirli T Tutar E Çiftçi E Ince E Ileri T Atalay S
Abstract: No Abstract available
Pubmed Id: 21955009
22. Kharasch ED et al. Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics. Clinical pharmacology and therapeutics. 2012
Authors: Kharasch ED Whittington D Ensign D Hoffer C Bedynek PS Campbell S Stubbert K Crafford A London A Kim T
Abstract: Mechanisms by which efavirenz diminishes methadone plasma concentrations are unknown. This investigation determined efavirenz influence on clinical methadone disposition and miosis, intravenous and oral alfentanil clearance (hepatic and intestinal cytochrome P450 3A4/5 (CYP3A4/5) activity), fexofenadine disposition (intestinal transporters activity), and efavirenz clearance and 8-hydroxylation (CYP2B6 activity), and human hepatocyte effects. Efavirenz induced systemic and oral alfentanil clearances two- to fivefold and induced efavirenz 8-hydroxylation. Efavirenz stereoselectively decreased methadone plasma concentrations 50-70%. Methadone systemic and oral clearances, hepatic clearance and extraction ratio, N-demethylation, and metabolite formation clearance were stereoselectively increased two- to threefold. Bioavailability decreased. Efavirenz shifted methadone concentration-miosis curves leftward and upward. Efavirenz induced hepatocyte CYP2B6 and CYP3A4 expression, activity, and methadone N-demethylation. Results show that efavirenz coinduced hepatic CYP2B6 and CYP3A4/5, coinduced hepatic and intestinal CYP3A4/5, and coinduced gastrointestinal CYP3A4/5 and efflux transporters. Methadone disposition was most consistent with efavirenz induction of hepatic CYP2B6-mediated methadone N-demethylation. Efavirenz may alter methadone pharmacodynamics.
Pubmed Id: 22398970
23. Ivanyuk A et al. Renal Drug Transporters and Drug Interactions. Clinical pharmacokinetics. 2017
Authors: Ivanyuk A Livio F Biollaz J Buclin T
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Pubmed Id: 28210973
24. Hanke N et al. PBPK Models for CYP3A4 and P-gp DDI Prediction: A Modeling Network of Rifampicin, Itraconazole, Clarithromycin, Midazolam, Alfentanil, and Digoxin. CPT: pharmacometrics & systems pharmacology. 2018
Authors: Hanke N Frechen S Moj D Britz H Eissing T Wendl T Lehr T
Abstract: According to current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance documents, physiologically based pharmacokinetic (PBPK) modeling is a powerful tool to explore and quantitatively predict drug-drug interactions (DDIs) and may offer an alternative to dedicated clinical trials. This study provides whole-body PBPK models of rifampicin, itraconazole, clarithromycin, midazolam, alfentanil, and digoxin within the Open Systems Pharmacology (OSP) Suite. All models were built independently, coupled using reported interaction parameters, and mutually evaluated to verify their predictive performance by simulating published clinical DDI studies. In total, 112 studies were used for model development and 57 studies for DDI prediction. 93% of the predicted area under the plasma concentration-time curve (AUC) ratios and 94% of the peak plasma concentration (C) ratios are within twofold of the observed values. This study lays a cornerstone for the qualification of the OSP platform with regard to reliable PBPK predictions of enzyme-mediated and transporter-mediated DDIs during model-informed drug development. All presented models are provided open-source and transparently documented.
Pubmed Id: 30091221
25. Yoshida K et al. Accurate Estimation of In Vivo Inhibition Constants of Inhibitors and Fraction Metabolized of Substrates with Physiologically Based Pharmacokinetic Drug-Drug Interaction Models Incorporating Parent Drugs and Metabolites of Substrates with Cluster Newton Method. Drug metabolism and disposition: the biological fate of chemicals. 2018
Authors: Yoshida K Maeda K Konagaya A Kusuhara H
Abstract: The accurate estimation of "in vivo" inhibition constants () of inhibitors and fraction metabolized () of substrates is highly important for drug-drug interaction (DDI) prediction based on physiologically based pharmacokinetic (PBPK) models. We hypothesized that analysis of the pharmacokinetic alterations of substrate metabolites in addition to the parent drug would enable accurate estimation of in vivoandTwenty-four pharmacokinetic DDIs caused by P450 inhibition were analyzed with PBPK models using an emerging parameter estimation method, the cluster Newton method, which enables efficient estimation of a large number of parameters to describe the pharmacokinetics of parent and metabolized drugs. For each DDI, two analyses were conducted (with or without substrate metabolite data), and the parameter estimates were compared with each other. In 17 out of 24 cases, inclusion of substrate metabolite information in PBPK analysis improved the reliability of bothandImportantly, the estimatedfor the same inhibitor from different DDI studies was generally consistent, suggesting that the estimatedfrom one study can be reliably used for the prediction of untested DDI cases with different victim drugs. Furthermore, a large discrepancy was observed between the reported in vitroand the in vitro estimates for some inhibitors, and the current in vivoestimates might be used as reference values when optimizing in vitro-in vivo extrapolation strategies. These results demonstrated that better use of substrate metabolite information in PBPK analysis of clinical DDI data can improve reliability of top-down parameter estimation and prediction of untested DDIs.
Pubmed Id: 30135241

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