QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of ciprofloxacin, lidocaine and itraconazole. Please also consult the relevant specialist information.
The changes in exposure mentioned relate to changes in the plasma concentration-time curve [AUC]. We did not detect any change in exposure to ciprofloxacin. We cannot currently estimate the influence of lidocaine and itraconazole. Lidocaine exposure increases to 534%, when combined with ciprofloxacin (244%) and itraconazole (185%). This can lead to increased side effects. Itraconazole exposure increases to 115%, when combined with ciprofloxacin (115%). We cannot currently estimate the influence of lidocaine.
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Ciprofloxacin has a mean oral bioavailability [ F ] of 70%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather short at 3.5 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is very weak at 30%. About 55.0% of an administered dose is excreted unchanged via the kidneys and this proportion is seldom changed by interactions. The metabolism mainly takes place via CYP1A2 and the active transport takes place partly via BCRP, OATP1A2 and PGP.
Lidocaine has a low oral bioavailability [ F ] of 29%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is rather short at 2.9 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is rather weak at 70% and the volume of distribution [ Vd ] is very large at 165 liters, However, since the substance has a high hepatic extraction rate of 0.71, only changes in the liver blood flow [Q] are relevant. The metabolism takes place via CYP1A2 and CYP3A4, among others.
Itraconazole has a mean oral bioavailability [ F ] of 55%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is 21 hours and constant plasma levels [ Css ] are reached after approximately 84 hours. The protein binding [ Pb ] is very strong at 99.8% and the volume of distribution [ Vd ] is very large at 796 liters, which is why, with a mean hepatic extraction rate of 0.44, both liver blood flow [Q] and a change in protein binding [Pb] are relevant. The metabolism mainly takes place via CYP3A4 and the active transport takes place in particular via PGP.
|Serotonergic Effects a||0||Ø||Ø||Ø|
Rating: According to our knowledge, neither ciprofloxacin, lidocaine nor itraconazole increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø||Ø|
Rating: According to our findings, neither ciprofloxacin, lidocaine nor itraconazole increase anticholinergic activity.
QT time prolongation
Rating: In combination, ciprofloxacin and itraconazole can potentially trigger ventricular arrhythmias of the torsades de pointes type. We do not know of any QT-prolonging potential for lidocaine.
General adverse effects
|Side effects||∑ frequency||cip||lid||itr|
|Upper respiratory infection||8.0 %||n.a.||n.a.||8.0|
|Peripheral edema||4.0 %||n.a.||n.a.||4.0|
Diarrhea (3.8%): itraconazole, ciprofloxacin
Abdominal pain (2.9%): itraconazole
Pancreatitis: itraconazole, ciprofloxacin
Clostridium difficile diarrhea: ciprofloxacin
Gastrointestinal hemorrhage: ciprofloxacin
Hypotension (3%): lidocaine
Hypertension (3%): itraconazole
Myocardial infarction: ciprofloxacin
Heart failure: itraconazole
Nasal discharge (3%): ciprofloxacin
Pulmonary edema: itraconazole
Dizziness (2.6%): itraconazole
Disturbance of attention: ciprofloxacin
Memory impairment: ciprofloxacin
Peripheral neuropathy: ciprofloxacin
Pseudotumor cerebri: ciprofloxacin
Raised intracranial pressure: ciprofloxacin
Fever (2.5%): itraconazole
Fatigue (2.3%): itraconazole
Hepatotoxicity: itraconazole, ciprofloxacin
Liver failure: ciprofloxacin
Hypersensitivity reaction: itraconazole, ciprofloxacin
Anaphylactic reaction: lidocaine
Toxic epidermal necrolysis: ciprofloxacin
Stevens johnson syndrome: ciprofloxacin
Hemorrhagic cystitis: ciprofloxacin
Renal failure: ciprofloxacin
Tubulointerstitial nephritis: ciprofloxacin
Aplastic anemia: ciprofloxacin
Hemolytic anemia: ciprofloxacin
Hearing loss: itraconazole
Myasthenia gravis: ciprofloxacin
Rupture of tendon: ciprofloxacin
Aortic aneurysm: ciprofloxacin
Based on your
Abstract: To account for a 40% lowering of the systemic clearance of lignocaine by propranolol treatment it has been proposed that propranolol reduces liver blood flow by 25% and causes a 50% decrease in the intrinsic clearance of lignocaine by enzyme inhibition. In theory, the contribution of direct enzyme inhibition is best evaluated using oral administration of lignocaine when models of hepatic drug clearance predict that propranolol could increase the AUCpo of lignocaine by 100-140%. This hypothesis was tested in six healthy men who received 200 mg lignocaine HCl X H2O orally with and without propranolol pre-treatment (80 mg twice daily for 3 days). Propranolol treatment increased the mean plasma AUCpo of lignocaine by 113 +/- 58 s.d.% (P less than 0.005); it increased the peak plasma lignocaine concentration by 79 +/- 50 s.d.% (P less than 0.025) and it prolonged the elimination half-life of lignocaine by 20 +/- 13 s.d.% (P less than 0.05). Propranolol treatment lowered indocyanine green clearance by 11 +/- 15 s.d.%, but this change was not significant statistically. These experimental results are in accord with the theoretical predictions suggesting that propranolol lowers the systemic clearance of lignocaine mainly by direct inhibition of its metabolism rather than by a lowering of the hepatic blood flow.
Abstract: No Abstract available
Abstract: The pharmacokinetics of intravenous ciprofloxacin and its metabolites were characterized in 42 subjects with various degrees of renal function (group 1, Clcr (mL/min/1.73 m2) > 90, n = 10; group 2, Clcr 61-90, n = 11; group 3, Clcr 31-60, n = 11; group 4, Clcr < or = 30, n = 10). The dosage regimens were-groups 1 and 2: 400 mg i.v. at 8 hourly intervals; group 3: 400 mg i.v. at 12 hourly intervals and group 4: 300 mg i.v. at 12 hourly intervals. Subjects received a single dose on days 1 and 5 and multiple doses on days 2-4. Multiple plasma and urine samples were collected on days 1 and 5 for the analysis of ciprofloxacin and its metabolites (M1, M2 and M3). Plasma concentrations (Cmax and AUC) of ciprofloxacin and its M1 and M2 metabolites were significantly increased in subjects with reduced Clcr values (Clcr < 60 mL/min/1.73 m2) compared with normal subjects (Clcr > 90 mL/min/1.73 m2). A positive correlation was observed between ciprofloxacin clearance (Cl) and Clcr with a slope of 0.29 (r2 = 0.78) and between renal clearance (Clr) and Clcr with a slope of 0.19 (r2 = 0.84). For patients with severe infections a dosage regimen of 400 mg iv 8 hourly is appropriate in patients with Clcr > 60 mL/min/1.73 m2. In patients with Clcr values of 31-60 mL/min/1.73 m2 a dosage regimen of 400 mg 12 hourly provides similar plasma concentrations to those observed for subjects with Clcr 61-90 mL/min/1.73 m2 receiving 400 mg 8 hourly. Based on modeling of the plasma concentrations in subjects with Clcr < or = 30 ml/min/1.73 m2, a dosage regimen of 400 mg every 24 h will provide plasma concentrations similar to those observed in subjects with Clcr between 61-90 mL/min/1.73 m2 given 400 mg every 8 h.
Abstract: Lignocaine is metabolized by cytochrome P450 3A4 enzyme (CYP3A4), and has a moderate to high extraction ratio resulting in oral bioavailability of 30%. We have studied the possible effect of two inhibitors of CYP3A4, erythromycin and itraconazole, on the pharmacokinetics of oral lignocaine in nine volunteers using a cross-over study design. The subjects were given erythromycin orally (500 mg three times a day), itraconazole (200 mg once a day) or placebo for four days. On day 4, each subject ingested a single dose of 1 mg/kg of oral lignocaine. Plasma samples were collected until 10 hr and concentrations of lignocaine and its major metabolite, monoethylglycinexylidide were measured by gas chromatography. Both erythromycin and itraconazole increased the area under the lignocaine plasma concentration-time curve [AUC(0-infinity)] and lignocaine peak concentrations by 40-70% (P<0.05). Compared to placebo and itraconazole, erythromycin increased monoethylglycinexylidide peak concentrations by approximately 40% (P<0.01) and AUC(0-infinity) by 60% (P<0.01). The clinical implication of this study is that erythromycin and itraconazole may significantly increase the plasma concentrations and toxicity of oral lignocaine. The extent of the interaction of lignocaine with these CYP3A4 inhibitors was, however, less than that of, e.g. midazolam or buspirone, and it did not correlate with the CYP3A4 inhibiting potency of erythromycin and itraconazole.
Abstract: STUDY OBJECTIVE: To compare the rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin administration. DESIGN: Retrospective database analysis. INTERVENTION: Evaluation of reported rates of torsades de pointes in patients who received these quinolones between January 1, 1996, and May 2, 2001. MEASUREMENTS AND MAIN RESULTS: In the United States, 25 cases of torsades de pointes associated with these quinolones (ciprofloxacin 2, ofloxacin 2, levofloxacin 13, gatifloxacin 8, moxifloxacin 0) were identified. Ciprofloxacin was associated with a significantly lower rate of torsades de pointes (0.3 cases/10 million prescriptions, 95% confidence interval [CI] 0.0-1.1) than levofloxacin (5.4/10 million, 95% CI 2.9-9.3, p<0.001) or gatifloxacin (27/10 million, 95% CI 12-53, p<0.001 for comparison with ciprofloxacin or levofloxacin). When the analysis was limited to the first 16 months after initial U.S. approval of the agent, the rates for levofloxacin (16/10 million) and gatifloxacin (27/10 million) were similar (p>0.5). CONCLUSION: Levofloxacin should be administered with caution in patients with risk factors for QT prolongation. Gatifloxacin should be avoided in the same patient population, and the recommended dosage of 400 mg/day should not be exceeded.
Abstract: Ciprofloxacin has been widely used for treating infections and has been found to have very low cardiovascular side effects. QTc prolongation with the use of ciprofloxacin is yet to be reported in literature. A case report highlighting QTc prolongation by use of ciprofloxacin is being presented.
Abstract: Itraconazole (ITZ) is a potent inhibitor of CYP3A in vivo. However, unbound plasma concentrations of ITZ are much lower than its reported in vitro Ki, and no clinically significant interactions would be expected based on a reversible mechanism of inhibition. The purpose of this study was to evaluate the reasons for the in vitro-in vivo discrepancy. The metabolism of ITZ by CYP3A4 was studied. Three metabolites were detected: hydroxy-itraconazole (OH-ITZ), a known in vivo metabolite of ITZ, and two new metabolites: keto-itraconazole (keto-ITZ) and N-desalkyl-itraconazole (ND-ITZ). OHITZ and keto-ITZ were also substrates of CYP3A4. Using a substrate depletion kinetic approach for parameter determination, ITZ exhibited an unbound K(m) of 3.9 nM and an intrinsic clearance (CLint) of 69.3 ml.min(-1).nmol CYP3A4(-1). The respective unbound Km values for OH-ITZ and keto-ITZ were 27 nM and 1.4 nM and the CLint values were 19.8 and 62.5 ml.min(-1).nmol CYP3A4(-1). Inhibition of CYP3A4 by ITZ, OH-ITZ, keto-ITZ, and ND-ITZ was evaluated using hydroxylation of midazolam as a probe reaction. Both ITZ and OH-ITZ were competitive inhibitors of CYP3A4, with unbound Ki (1.3 nM for ITZ and 14.4 nM for OH-ITZ) close to their respective Km. ITZ, OH-ITZ, keto-ITZ and ND-ITZ exhibited unbound IC50 values of 6.1 nM, 4.6 nM, 7.0 nM, and 0.4 nM, respectively, when coincubated with human liver microsomes and midazolam (substrate concentration < Km). These findings demonstrate that ITZ metabolites are as potent as or more potent CYP3A4 inhibitors than ITZ itself, and thus may contribute to the inhibition of CYP3A4 observed in vivo after ITZ dosing.
Abstract: Inhibitors of CYP3A4 (cytochrome P450 3A4) have a minor effect on lidocaine pharmacokinetics. We studied the effect of coadministration of the antidepressant fluvoxamine (CYP1A2 inhibitor) and antimicrobial drug erythromycin (CYP3A4 inhibitor) on lidocaine pharmacokinetics in a double-blind, randomized, three-way crossover study. Nine volunteers ingested daily 100 mg fluvoxamine and placebo, 100 mg fluvoxamine and 1500 mg erythromycin, or their corresponding placebos for 5 days. On day 6, 1.5 mg/kg lidocaine was administered IV over 60 min. Concentrations of lidocaine and its major metabolite monoethylglycinexylidide were measured for 10 h. Fluvoxamine alone decreased the clearance of lidocaine by 41% (P < 0.001) and prolonged its elimination half-life from 2.6 to 3.5 h (P < 0.01). During the combination of fluvoxamine and erythromycin, lidocaine clearance was 53% smaller than during placebo (P < 0.001) and 21% smaller than during fluvoxamine alone (P < 0.05). During the combination phase the half-life of lidocaine (4.3 h) was longer than during the placebo (2.6 h; P < 0.001) or fluvoxamine (3.5 h; P < 0.01). We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces elimination of lidocaine and may increase the risk of lidocaine toxicity. Concomitant use of both fluvoxamine and a CYP3A4 inhibitor such as erythromycin can further increase plasma lidocaine concentrations by decreasing its clearance.
Abstract: BACKGROUND AND OBJECTIVE: Recent studies have suggested that cytochrome P-450 isoenzyme 1A2 has an important role in lidocaine biotransformation. We have studied the effect of a cytochrome P-450 1A2 inhibitor, ciprofloxacin, on the pharmacokinetics of lidocaine. METHODS: In a randomized, double-blinded, cross-over study, nine healthy volunteers ingested for 2.5 days 500 mg oral ciprofloxacin or placebo twice daily. On day 3, they received a single dose of 1.5 mg kg[-1] lidocaine intravenously over 60 min. Plasma concentrations of lidocaine, 3-hydroxylidocaine and monoethylglycinexylidide were determined for 11 h after the start of the lidocaine infusion. RESULTS: Ciprofloxacin increased the mean peak concentration and area under plasma concentration-time curve of lidocaine by 12% (range [-6] to+46%; P<0.05) and 26% (8--59%; P 0.01), respectively. The mean plasma clearance of lidocaine was decreased by ciprofloxacin by 22% (7--38%; P<0.01). Ciprofloxacin decreased the area under the plasma concentration-time curve of monoethylglycinexylidide by 21% (P<0.01) and that of 3-hydroxylidocaine by 14% (P< 0.01). CONCLUSION: The plasma decay of intravenously administered lidocaine is modestly delayed by concomitantly administered ciprofloxacin. Ciprofloxacin may increase the systemic toxicity of lidocaine.
Abstract: The new respiratory fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and on the horizon, garenoxacin) offer many improved qualities over older agents such as ciprofloxacin. These include retaining excellent activity against Gram-negative bacilli, with improved Gram-positive activity (including Streptococcus pneumoniae and Staphylococcus aureus). In addition, gatifloxacin, moxifloxacin and garenoxacin all demonstrate increased anaerobic activity (including activity against Bacteroides fragilis). The new fluoroquinolones possess greater bioavailability and longer serum half-lives compared with ciprofloxacin. The new fluoroquinolones allow for once-daily administration, which may improve patient adherence. The high bioavailability allows for rapid step down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve quality of life of patients. Clinical trials involving the treatment of community-acquired respiratory infections (acute exacerbations of chronic bronchitis, acute sinusitis, and community-acquired pneumonia) demonstrate high bacterial eradication rates and clinical cure rates. In the treatment of community-acquired respiratory tract infections, the various new fluoroquinolones appear to be comparable to each other, but may be more effective than macrolide or cephalosporin-based regimens. However, additional data are required before it can be emphatically stated that the new fluoroquinolones as a class are responsible for better outcomes than comparators in community-acquired respiratory infections. Gemifloxacin (except for higher rates of hypersensitivity), levofloxacin, and moxifloxacin have relatively mild adverse effects that are more or less comparable to ciprofloxacin. In our opinion, gatifloxacin should not be used, due to glucose alterations which may be serious. Although all new fluoroquinolones react with metal ion-containing drugs (antacids), other drug interactions are relatively mild compared with ciprofloxacin. The new fluoroquinolones gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin have much to offer in terms of bacterial eradication, including activity against resistant respiratory pathogens such as penicillin-resistant, macrolide-resistant, and multidrug-resistant S. pneumoniae. However, ciprofloxacin-resistant organisms, including ciprofloxacin-resistant S. pneumoniae, are becoming more prevalent, thus prudent use must be exercised when prescribing these valuable agents.
Abstract: Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.
Abstract: PURPOSE: The objective is to confirm if the prediction of the drug-drug interaction using a physiologically based pharmacokinetic (PBPK) model is more accurate. In vivo Ki values were estimated using PBPK model to confirm whether in vitro Ki values are suitable. METHOD: The plasma concentration-time profiles for the substrate with coadministration of an inhibitor were collected from the literature and were fitted to the PBPK model to estimate the in vivo Ki values. The AUC ratios predicted by the PBPK model using in vivo Ki values were compared with those by the conventional method assuming constant inhibitor concentration. RESULTS: The in vivo Ki values of 11 inhibitors were estimated. When the in vivo Ki values became relatively lower, the in vitro Ki values were overestimated. This discrepancy between in vitro and in vivo Ki values became larger with an increase in lipophilicity. The prediction from the PBPK model involving the time profile of the inhibitor concentration was more accurate than the prediction by the conventional methods. CONCLUSION: A discrepancy between the in vivo and in vitro Ki values was observed. The prediction using in vivo Ki values and the PBPK model was more accurate than the conventional methods.
Abstract: BACKGROUND: Liver cirrhosis is a progressive disease characterized by loss of functional hepatocytes with concomitant connective tissue and nodule formation in the liver. The morphological and physiological changes associated with the disease substantially affect drug pharmacokinetics. Whole-body physiologically based pharmacokinetic (WB-PBPK) modelling is a predictive technique that quantitatively relates the pharmacokinetic parameters of a drug to such (patho-)physiological conditions. OBJECTIVE: To extend an existing WB-PBPK model, based on the physiological changes associated with liver cirrhosis, which allows for prediction of drug pharmacokinetics in patients with liver cirrhosis. METHODS: The literature was searched for quantitative measures of the physiological changes associated with the presence of Child-Pugh class A through C liver cirrhosis. The parameters that were included were the organ blood flows, cardiac index, plasma binding protein concentrations, haematocrit, functional liver volume, hepatic enzymatic activity and glomerular filtration rate. Predictions of pharmacokinetic profiles and parameters were compared with literature data for the model compounds alfentanil, lidocaine (lignocaine), theophylline and levetiracetam. RESULTS: The predicted versus observed plasma concentration-time profiles for alfentanil and lidocaine were similar, such that the pharmacokinetic changes associated with Child-Pugh class A, B and C liver cirrhosis were adequately described. The theophylline elimination half-life was greatly increased in Child-Pugh class B and C patients compared with controls, as predicted by the model. Levetiracetam urinary excretion was consistently reduced with disease progression and very closely resembled observed values. CONCLUSION: Consideration of the physiological differences between healthy individuals and patients with liver cirrhosis was important for the simulation of drug pharmacokinetics in this compromised group. The WB-PBPK model was altered to incorporate these physiological differences with the result of adequate simulation of drug pharmacokinetics. The information provided in this study will allow other researchers to further validate this liver cirrhosis model within a WB-PBPK model.
Abstract: Fluoroquinolone antimicrobial drugs are absorbed efficiently after oral administration despite of their hydrophilic nature, implying an involvement of carrier-mediated transport in their membrane transport process. It has been that several fluoroquinolones are substrates of organic anion transporter polypeptides OATP1A2 expressed in human intestine derived Caco-2 cells. In the present study, to clarify the involvement of OATP in intestinal absorption of ciprofloxacin, the contribution of Oatp1a5, which is expressed at the apical membranes of rat enterocytes, to intestinal absorption of ciprofloxacin was investigated in rats. The intestinal membrane permeability of ciprofloxacin was measured by in situ and the vascular perfused closed loop methods. The disappeared and absorbed amount of ciprofloxacin from the intestinal lumen were increased markedly in the presence of 7,8-benzoflavone, a breast cancer resistance protein inhibitor, and ivermectin, a P-glycoprotein inhibitor, while it was decreased significantly in the presence of these inhibitors in combination with naringin, an Oatp1a5 inhibitor. Furthermore, the Oatp1a5-mediated uptake of ciprofloxacin was saturable with a K(m) value of 140 µm, and naringin inhibited the uptake with an IC(50) value of 18 µm by Xenopus oocytes expressing Oatp1a5. Naringin reduced the permeation of ciprofloxacin from the mucosal-to-serosal side, with an IC(50) value of 7.5 µm by the Ussing-type chamber method. The estimated IC(50) values were comparable to that of Oatp1a5. These data suggest that Oatp1a5 is partially responsible for the intestinal absorption of ciprofloxacin. In conclusion, the intestinal absorption of ciprofloxacin could be affected by influx transporters such as Oatp1a5 as well as the efflux transporters such as P-gp and Bcrp.
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.
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.
Abstract: It has been shown that arterial (central) and venous (peripheral) plasma drug concentrations can be very different. While pharmacokinetic studies typically measure drug concentrations from the peripheral vein such as the arm vein, physiologically based pharmacokinetic (PBPK) models generally output simulated concentrations from the central venous compartment that physiologically represents the right atrium, a merge of the superior and inferior vena cava. In this study, a physiologically based peripheral forearm sampling site model was developed and verified using nicotine, ketamine, lidocaine, and fentanyl as model drugs. This verified model allows output of simulated peripheral venous concentrations that can be meaningfully compared with observed pharmacokinetic data from the arm vein. The generalized effect of PBPK model sampling site on simulation output was investigated. Drugs and metabolites with large volumes of distribution showed considerable concentration discrepancy between the simulated central venous compartment and the peripheral arm vein after intravenous or oral administration, resulting in significant differences in values forand time taken to reach() In addition, the simulated central venous metabolite profile showed an unexpected profile that was not observed in the peripheral arm vein. Using fentanyl as a model compound, we show that using the wrong sampling site in PBPK models can lead to biased model evaluation and subsequent erroneous model parameter optimization. Such an error in model parameters along with the discrepant sampling site could dramatically mislead the pharmacokinetic prediction in unstudied clinical scenarios, affecting the assessment of drug safety and efficacy. Overall, this study shows that PBPK model publications should specify the model sampling sites and match them with those employed in clinical studies. SIGNIFICANCE STATEMENT: Our study shows that sampling from the central venous compartment (right atrium) during physiologically based pharmacokinetic model development gives rise to biased model evaluation and erroneous model parameterization when observed data are collected from the peripheral arm vein. This can lead to a clinically significant error in predictions of plasma concentration-time profiles in unstudied scenarios. To address this error, we developed and verified a novel peripheral sampling site model to simulate arm vein drug concentrations that can be applied to different drug dosing scenarios.