QT time prolongation
Adverse drug events
|Elevated alkaline phosphatase|
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Explanations of the substances for patients
We have no additional warnings for the combination of aliskiren, cimetidine and rifampicin. Please also consult the relevant specialist information.
The changes in exposure mentioned relate to changes in the plasma concentration-time curve [AUC]. Aliskiren exposure is reduced to 50%, when combined with cimetidine (103%) and rifampicin (49%). This can be associated with reduced effectiveness. We did not detect any change in exposure to cimetidine, when combined with aliskiren (100%). We cannot currently estimate the influence of rifampicin. We did not detect any change in exposure to rifampicin. We cannot currently estimate the influence of aliskiren and cimetidine.
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Aliskiren has a low oral bioavailability [ F ] of 3%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is rather long at 26 hours and constant plasma levels [ Css ] are only reached after more than 104 hours. The protein binding [ Pb ] is rather weak at 49% and the volume of distribution [ Vd ] is very large at 133 liters. Since the substance has a low hepatic extraction rate of 0.14, displacement from protein binding [Pb] in the context of an interaction can increase exposure. About 23.0% of an administered dose is excreted unchanged via the kidneys and this proportion is seldom changed by interactions. The metabolism mainly takes place via CYP3A4 and the active transport takes place partly via OATP1A2, OATP2B1 and PGP.
Cimetidine has a mean oral bioavailability [ F ] of 65%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather short at 1.6333333 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is very weak at 19% and the volume of distribution [ Vd ] is very large at 91 liters. The metabolism does not take place via the common cytochromes and the active transport takes place partly via BCRP and PGP.
Rifampicin has a high oral bioavailability [ F ] of 90%, which is why the maximum plasma levels [Cmax] tend to change little during 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 moderately strong at 75% and the volume of distribution [ Vd ] is very large at 101 liters. The metabolism does not take place via the common cytochromes and the active transport takes place partly via OATP1B1, OATP1B3 and PGP.
|Serotonergic Effects a||0||Ø||Ø||Ø|
Rating: According to our knowledge, neither aliskiren, cimetidine nor rifampicin increase serotonergic activity.
|Kiesel & Durán b||1||Ø||+||Ø|
Recommendation: As a precaution, attention should be paid to anticholinergic symptoms, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Cimetidine only has a mild effect on the anticholinergic system. The risk of anticholinergic syndrome with this medication is rather low if the dosage is in the usual range. According to our findings, neither aliskiren nor rifampicin increase anticholinergic activity.
QT time prolongation
Recommendation: Please make sure that influenceable risk factors are minimized. Electrolyte disturbances such as low levels of calcium, potassium and magnesium should be compensated for. The lowest effective dose of cimetidine should be used.
Rating: Cimetidine can potentially prolong the QT time and if there are risk factors, arrhythmias of the type torsades de pointes can be favored. We do not know of any QT-prolonging potential for aliskiren and rifampicin.
General adverse effects
|Side effects||∑ frequency||ali||cim||rif|
|Elevated alkaline phosphatase||10.0 %||n.a.||n.a.||10.0|
|Elevated GGT||10.0 %||n.a.||n.a.||10.0|
|Elevated transaminases||10.0 %||n.a.||n.a.||10.0|
|Elevated serum creatinine||1.0 %||+||n.a.||n.a.|
|Loss of appetite||1.0 %||n.a.||n.a.||+|
Pancreatitis: cimetidine, rifampicin
Allergic skin reactions like pruritus and rash: aliskiren
Anaphylactic reaction: rifampicin
Stevens johnson syndrome: aliskiren
Toxic epidermal necrolysis: aliskiren
Renal failure: aliskiren
Thrombotic thrombocytopenic purpura: rifampicin
Liver failure: rifampicin
Optic neuritis: rifampicin
Based on your
Abstract: We investigated the pharmacokinetics of rifampicin and its major metabolites, 25-desacetylrifampicin and 3-formylrifampicin, in two groups of six patients with active pulmonary tuberculosis, who received either multiple oral or intravenous rifampicin therapy in combination with intravenous isoniazid and ethambutol. Serum concentrations of rifampicin were each determined after a single oral and intravenous test dose of 600 mg rifampicin at the beginning and after 1 and 3 weeks of tuberculostatic treatment. Analysis of rifampicin and its metabolites was performed by high-pressure liquid chromatography. It was found that, due to autoinduction of its metabolizing hepatic enzymes, the systemic clearance of rifampicin increased from 5.69 to 9.03 l/h after 3 weeks of multiple dosing. The volume of distribution of the drug was constant over the period of this study. The bioavailability of the active, orally administered rifampicin decreased from 93% after the first single oral dose to 68% after 3 weeks of oral and intravenous rifampicin therapy. Relating to the increase in systemic (hepatic) clearance, a bioavailability no lower than 90% can be predicted. The reduction to 68% indicates that, in addition to an increase of hepatic metabolism, an induction of a prehepatic "first-pass" effect resulted from multiple rifampicin doses. Our study of rifampicin metabolites confirm that prehepatic metabolism was induced, since a higher metabolic ratio resulted after the oral doses than after the intravenous rifampicin test doses. A preabsorptive process can therefore be excluded as a cause of reduced bioavailability.
Abstract: Recently, the use of astemizole and terfenadine, both non-sedating H1-antihistamines, caused considerable concern. Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia. The increased risk of both H1-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine. To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied. Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals. The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low. Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.
Abstract: Astemizole (Hismanal), an antihistamine agent, has been reported to be associated with ventricular arrhythmias. In this paper we present a case of QT prolongation and torsades de pointes (TdP) in a 77-year-old woman who had been taking astemizole (10 mg/day) for 6 months because of allergic skin disease. At the time of admission, the serum concentration of astemizole and its metabolites was markedly elevated at 15.85 ng/ml, approximately 3 times the normal level. The patient was also taking cimetidine, a known inhibitor of cytochrome P-450 enzymatic activity, and during her admission was diagnosed as having vasospastic angina. To the best of our knowledge, this is the first report of astemizole-induced QT prolongation and TdP in Japan.
Abstract: The antibiotics rifamycin SV and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and rifampicin on hepatic organic anion elimination.
Abstract: Rifampin, a member of the rifamycin class of antibiotics, is well known for its ability to induce drug-metabolizing enzymes and transporters, through activation of the pregnane X receptor. Available data suggest rifampin entry into hepatocytes may be transporter-mediated. Accordingly, it is therefore plausible that modulation of the achievable intracellular concentration of rifampin by drug uptake transporters would influence the degree of induction. In this study, we expressed an array of known hepatic uptake transporters to show the key hepatic rifampin uptake transporters are liver-specific members of the organic anion transporting polypeptide family (OATP). Indeed, both OATP-C and OATP8 seemed capable of mediating rifampin uptake into HeLa cells. OATP-C, however, seemed to have far greater affinity and capacity for rifampin transport. In addition, several allelic variants of OATP-C known to be present among European and African Americans were found to have markedly decreased rifampin transport activity. In cell-based, transactivation assays, OATP-C expression was associated with increased cellular rifampin retention as well as potentiation of PXR reporter gene activity. This is the first demonstration of an uptake transporter such as OATP-C, in modulating PXR function, and sheds important new insight into our understanding of the molecular determinants of PXR-mediated inductive processes.
Abstract: Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ultraviolet (HPLC/UV) methods. Renal tubular secretion (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: If tuberculosis therapy is to be shortened it is imperative that the sterilising activity of current and future anti-tuberculosis drugs is enhanced. Intracellular Mycobacterium tuberculosis (MTB) phagocytosed by macrophages may be a key subpopulation of bacteria that are less readily eliminated by therapy. Here we investigate whether macrophages provide MTB with a pharmacological sanctuary site, making them less susceptible to chemotherapy than extracellular bacilli. Intracellular drug activity was determined by a novel colorimetric method that measures the ability of a drug to protect A-THP1 cells from infection-mediated cell death by H37Rv. Extracellular bactericidal activity was determined by the microplate alamar blue assay (MABA). Further, the effect of P-glycoprotein (P-gp) expressed on macrophages on the intracellular kill of H37Rv was assessed. To screen the anti-tuberculosis drugs for P-gp substrate specificity, their toxicity and cellular accumulation were determined in CEM and CEM(VBL100) cells. Intracellular and extracellular anti-tuberculosis drug activity following 7-day treatment with isoniazid (mean EC(50)+/-SD: 36.7+/-2.2 and 57.2+/-2.5 ng/mL, respectively) and ethambutol (243+/-95 and 263+/-12 ng/mL, respectively) were similar. However, for rifampicin a higher concentration was required to kill intracellular (148+/-32 ng/mL) versus extracellular (1.27+/-0.02 ng/mL) bacilli. The P-gp inhibitor tariquidar, significantly increased intracellular kill of H37Rv by ethambutol and rifampicin and both of these drugs were shown to be substrates for P-gp using the P-gp overexpressing CEM(VBL100) cells. We observed a large discrepancy between intracellular and extracellular activity of rifampicin (but not with isoniazid or ethambutol). Several factors could have accounted for this including inoculum size, media and cell-mediated metabolism. These factors make the comparison of intracellular and extracellular drug activity complex. However, the intracellular assay described here has potential for studying the impact of host proteins (such as drug transporters) on the intracellular activity of drugs, and has been used successfully here to demonstrate that both rifampicin and ethambutol are substrates for P-gp.
Abstract: BACKGROUND: Aliskiren is an orally active direct renin inhibitor approved for the treatment of hypertension. This study assessed the effects of renal impairment on the pharmacokinetics and safety of aliskiren alone and in combination with the angiotensin receptor antagonist irbesartan. METHODS: This open-label study enrolled 17 males with mild, moderate or severe renal impairment (creatinine clearance [CL(CR)] 50-80, 30-49 and <30 mL/minute, respectively) and 17 healthy males matched for age and bodyweight. Subjects received oral aliskiren 300 mg once daily on days 1-7 and aliskiren coadministered with irbesartan 300 mg on days 8-14. Plasma aliskiren concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry at frequent intervals up to 24 hours after dosing on days 1, 7 and 14. RESULTS: Renal clearance of aliskiren averaged 1280 +/- 500 mL/hour (mean +/- SD) in healthy subjects and 559 +/- 220, 312 +/- 75 and 243 +/- 186 mL/hour in patients with mild, moderate and severe renal impairment, respectively. At steady state (day 7), the geometric mean ratios (renal impairment : matched healthy volunteers) ranged from 1.21 to 2.05 for the area under the plasma concentration-time curve (AUC) over the dosage interval tau (24h) [AUC(tau)]) and from 0.83 to 2.25 for the maximum observed plasma concentration of aliskiren at steady state. Changes in exposure did not correlate with CL(CR), consistent with an effect of renal impairment on non-renal drug disposition. The observed large intersubject variability in aliskiren pharmacokinetic parameters was unrelated to the degree of renal impairment. Accumulation of aliskiren at steady state (indicated by the AUC from 0 and 24 hours [AUC(24)] on day 7 vs day 1) was similar in healthy subjects (1.79 [95% CI 1.24, 2.60]) and those with renal impairment (range 1.39-1.99). Coadministration with irbesartan did not alter the pharmacokinetics of aliskiren. Aliskiren was well tolerated when administered alone or with irbesartan. CONCLUSIONS: Exposure to aliskiren is increased by renal impairment but does not correlate with the severity of renal impairment (CL(CR)). This is consistent with previous data indicating that renal clearance of aliskiren represents only a small fraction of total clearance. Initial dose adjustment of aliskiren is unlikely to be required in patients with renal impairment.
Abstract: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
Abstract: This study investigated the potential pharmacokinetic interaction between the direct renin inhibitor aliskiren and modulators of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Aliskiren stimulated in vitro P-glycoprotein ATPase activity in recombinant baculovirus-infected Sf9 cells with high affinity (K(m) 2.1 micromol/L) and was transported by organic anion-transporting peptide OATP2B1-expressing HEK293 cells with moderate affinity (K(m) 72 micromol/L). Three open-label, multiple-dose studies in healthy subjects investigated the pharmacokinetic interactions between aliskiren 300 mg and digoxin 0.25 mg (n = 22), atorvastatin 80 mg (n = 21), or ketoconazole 200 mg bid (n = 21). Coadministration with aliskiren resulted in changes of <30% in AUC(tau) and C(max,ss) of digoxin, atorvastatin, o-hydroxy-atorvastatin, and rho-hydroxy-atorvastatin, indicating no clinically significant interaction with P-glycoprotein or CYP3A4 substrates. Aliskiren AUC(tau) was significantly increased by coadministration with atorvastatin (by 47%, P < .001) or ketoconazole (by 76%, P < .001) through mechanisms most likely involving transporters such as P-glycoprotein and organic anion-transporting peptide and possibly through metabolic pathways such as CYP3A4 in the gut wall. These results indicate that aliskiren is a substrate for but not an inhibitor of P-glycoprotein. On the basis of the small changes in exposure to digoxin and atorvastatin and the <2-fold increase in exposure to aliskiren during coadministration with atorvastatin and ketoconazole, the authors conclude that the potential for clinically relevant drug interactions between aliskiren and these substrates and/or inhibitors of P-glycoprotein/CPY3A4/OATP is low.
Abstract: This 12-week, multicenter, open-label study assessed the efficacy, pharmacokinetics and safety of a once-daily aliskiren in Japanese hypertensive patients with renal dysfunction. Patients (n=40, aged 20-80 years) with mean sitting diastolic blood pressure (msDBP) >or=95 and <110 mm Hg and serum creatinine between >or=1.3 and <3.0 mg per 100 ml in males or between >or=1.2 and <3.0 mg per 100 ml in females were eligible. Patients began therapy with a once-daily morning oral dose of 75 mg of aliskiren. In patients with inadequate blood pressure control (msDBP >or=90 or mean sitting systolic blood pressure [msSBP] >or=140 mm Hg) and without safety concerns (serum potassium >5.5 mEq l(-1) or an increase in serum creatinine >or=20%), the aliskiren dose was increased to 150 mg and then to 300 mg in sequential steps starting from Week 2. Efficacy was assessed as change in msSBP/msDBP from baseline to the Week 8 endpoint (with the last observation carried forward). The mean reduction from baseline to Week 8 endpoint was 13.9+/-16.6 and 11.6+/-9.7 mm Hg for msSBP and msDBP, respectively. At the Week 8 endpoint, 65% patients had achieved blood pressure response (msDBP <90 or a 10 mm Hg decrease or msSBP <140 or a 20 mm Hg decrease) and 30% had achieved blood pressure control (msSBP <140 mm Hg and msDBP <90 mm Hg). Aliskiren was well tolerated with no new safety concerns in Japanese hypertensive patients with renal dysfunction.
Abstract: In a randomized crossover study, 11 healthy volunteers took 100 mg (first dose 200 mg) of the antifungal drug itraconazole, a P-glycoprotein and CYP3A4 inhibitor, or placebo twice daily for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren, a renin inhibitor used in the treatment of hypertension. Itraconazole raised the peak plasma aliskiren concentration 5.8-fold (range, 1.1- to 24.3-fold; P < .001) and the area under the plasma aliskiren concentration-time curve 6.5-fold (range, 2.6- to 20.5-fold; P < .001) but had no significant effect on aliskiren elimination half-life. Itraconazole increased the amount of aliskiren excreted into the urine during 12 hours 8.0-fold (P < .001) and its renal clearance 1.2-fold (P = .042). Plasma renin activity 24 hours after aliskiren intake was 68% lower during the itraconazole phase than during the placebo phase (P = .011). In conclusion, itraconazole markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren. The interaction is probably mainly explained by inhibition of the P-glycoprotein-mediated efflux of aliskiren in the small intestine, with a minor contribution from inhibition of CYP3A4. Concomitant use of aliskiren and itraconazole is best avoided.
Abstract: The authors describe the drug-drug interaction between aliskiren and verapamil in healthy participants. Eighteen participants first received an oral dose of aliskiren 300 mg (highest recommended clinical dose) in period 1. After a 10-day washout period, the participants received verapamil 240 mg/d for 8 days (period 2). On day 8, the participants also received an oral dose of aliskiren 300 mg. Safety and pharmacokinetic analyses were performed during each treatment period. Concomitant administration of a single dose of aliskiren during steady-state verapamil resulted in an increase in plasma concentration of aliskiren. The mean increase in AUC(0-∞), AUC(last), and C(max) was about 2-fold. On day 8, in the presence of aliskiren, AUC(τ,ss) of R-norverapamil, R-verapamil, S-norverapamil, and S-verapamil was decreased by 10%, 16%, 10%, and 25%, respectively. Similarly, the C(max,ss) of R-norverapamil, R-verapamil, S-norverapamil, and S-verapamil was decreased by 13%, 18%, 12%, and 24%, respectively. Aliskiren did not affect the AUC(τ,ss) ratios of R-norverapamil/R-verapamil and S-norverapamil/S-verapamil. Aliskiren administered alone or in combination with verapamil was well tolerated in healthy participants. In conclusion, no dose adjustment is necessary when aliskiren is administered with moderate ABCB1 inhibitors such as verapamil (240 mg/d).
Abstract: To explore the clinical relevance of inhibition of multidrug resistance transporter 1 and organic anion transporting polypeptide transporter, a drug-drug interaction study was conducted using aliskiren and cyclosporine. This was an open-label, single-sequence, parallel-group, single-dose study in healthy subjects. Subjects (n = 14) first received aliskiren 75 mg orally (period 1), followed by aliskiren 75 mg + cyclosporine 200 mg (period 2) after a 7-day washout period, and aliskiren 75 mg + cyclosporine 600 mg (period 3) after a 14-day washout period. Safety and pharmacokinetics were analyzed during each period. The primary objective was to characterize pharmacokinetics of aliskiren (single-dose and combination with cyclosporine). The increases in area under the time-concentration curve from time 0 to infinity and maximum concentration associated with cyclosporine 200 mg or 600 mg were 4- to 5-fold and 2.5-fold, respectively. Mean half-life increased from 25 to 45 hours. Based on comparison to literature, a single-dose of aliskiren 75 mg did not alter the pharmacokinetics of cyclosporine. Aliskiren 75 mg was well tolerated. Combination with cyclosporine increased the number of adverse events, mainly hot flush and gastrointestinal symptoms, with no serious adverse events. Two adverse events led to withdrawal (ligament rupture, not suspected to be study-drug related; and vomiting, suspected to be study-drug related). Laboratory parameters, vital signs, and electrocardiographs showed no time- or treatment-related changes. As cyclosporine significantly altered the pharmacokinetics of aliskiren in humans, its use with aliskiren is not recommended.
Abstract: The human organic anion and cation transporters are classified within two SLC superfamilies. Superfamily SLCO (formerly SLC21A) consists of organic anion transporting polypeptides (OATPs), while the organic anion transporters (OATs) and the organic cation transporters (OCTs) are classified in the SLC22A superfamily. Individual members of each superfamily are expressed in essentially every epithelium throughout the body, where they play a significant role in drug absorption, distribution and elimination. Substrates of OATPs are mainly large hydrophobic organic anions, while OATs transport smaller and more hydrophilic organic anions and OCTs transport organic cations. In addition to endogenous substrates, such as steroids, hormones and neurotransmitters, numerous drugs and other xenobiotics are transported by these proteins, including statins, antivirals, antibiotics and anticancer drugs. Expression of OATPs, OATs and OCTs can be regulated at the protein or transcriptional level and appears to vary within each family by both protein and tissue type. All three superfamilies consist of 12 transmembrane domain proteins that have intracellular termini. Although no crystal structures have yet been determined, combinations of homology modelling and mutation experiments have been used to explore the mechanism of substrate recognition and transport. Several polymorphisms identified in members of these superfamilies have been shown to affect pharmacokinetics of their drug substrates, confirming the importance of these drug transporters for efficient pharmacological therapy. This review, unlike other reviews that focus on a single transporter family, briefly summarizes the current knowledge of all the functionally characterized human organic anion and cation drug uptake transporters of the SLCO and the SLC22A superfamilies.
Abstract: BACKGROUND AND OBJECTIVES: Aliskiren represents a novel class of orally active renin inhibitors. This study analyses the pharmacokinetics, tolerability and safety of single-dose aliskiren inpatients with end-stage renal disease (ESRD) undergoing haemodialysis. METHODS: Six ESRD patients and six matched healthy volunteers were enrolled in an open-label, parallel-group, single-sequence study. The ESRD patients underwent two treatment periods where 300 mg of aliskiren was administered 48 or 1 h before a standardized haemodialysis session (4 h, 1.4 m(2) high-flux filter, blood flow 300 mL/min, dialysate flow 500 mL/min). Washout was >10 days between both periods. Blood and dialysis samples were taken for up to 96 h postdose to determine aliskiren concentrations. RESULTS: Compared with the healthy subjects (1681 ± 1034 ng·h/mL), the area under the plasma concentration-time curve (AUC) from time zero to infinity was 61% (haemodialysis at 48 h) and 41% (haemodialysis at 1 h) higher in ESRD patients receiving single-dose aliskiren 300 mg. The maximum (peak) plasma drug concentration (481 ± 497 ng/mL in healthy subjects) was 17% higher (haemodialysis at 48 h) and 16% lower (haemodialysis at 1 h). In both treatment periods, dialysis clearance was below 2% of oral clearance and the mean fraction eliminated from circulation was 10 and 12% in period 1 and 2, respectively. Drug AUCs were similar in ESRD patients receiving aliskiren 1 or 48 h before dialysis. No severe adverse events occurred. CONCLUSION: The exposure of aliskiren is moderately higher in ESRD patients. Only a minor portion is removed by a typical haemodialysis session. Aliskiren exposure is not significantly affected by intermittent haemodialysis, suggesting that no dose adjustment is necessary in this population.
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: This study aimed to construct a physiologically based pharmacokinetic (PBPK) model of rifampicin that can accurately and quantitatively predict complex drug-drug interactions (DDIs) involving its saturable hepatic uptake and auto-induction. Using in silico and in vitro parameters, and reported clinical pharmacokinetic data, rifampicin PBPK model was built and relevant parameters for saturable hepatic uptake and UDP-glucuronosyltransferase (UGT) auto-induction were optimized by fitting. The parameters for cytochrome P450 (CYP) 3A and CYP2C9 induction by rifampicin were similarly optimized using clinical DDI data with midazolam and tolbutamide as probe substrates, respectively. For validation, our current PBPK model was applied to simulate complex DDIs with glibenclamide (a substrate of CYP3A/2C9 and hepatic organic anion transporting polypeptides (OATPs)). Simulated results were in quite good accordance with the observed data. Altogether, our constructed PBPK model of rifampicin demonstrates the robustness and utility in quantitatively predicting CYP3A/2C9 induction-mediated and/or OATP inhibition-mediated DDIs with victim drugs.
Abstract: The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg (8-12 mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of ≥ 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600 mg. Rifampicin maximum (peak) concentration (C) > 8.2 μg/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of ≥ 8 µg/mL. A higher rifampicin Cis required for severe forms TB such as TB meningitis, with C≥ 22 μg/mL and area under the concentration-time curve (AUC) from time zero to 6 h (AUC) ≥ 70 μg·h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35 mg/kg were found to be safe and well-tolerated over a period of 12 weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as C/MIC (minimum inhibitory concentration) and AUC/MIC.