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Exploratory effects of a strong CYP3A inhibitor (ketoconazole), a strong CYP3A inducer (rifampicin), and concomitant ethanol on piragliatin pharmacokinetics and pharmacodynamics in type 2 diabetic patients.
Zhi, J, Zhai, S, Georgy, A, Liang, Z, Boldrin, M
Journal of clinical pharmacology. 2016;(5):548-54
Abstract
Piragliatin is a CYP3A substrate; its inactive metabolite M4, formed through cytosolic reductase, is reversibly metabolized back to piragliatin through CYP3A. The impact of concomitant CYP3A modifiers thus cannot be predicted. Drinking alcohol under fasting conditions is associated with a recognized glucose-lowering effect, which might be synergistic with piragliatin's hypoglycemic effect. Two exploratory studies were conducted to examine these potential interactions in type 2 diabetes (T2D) patients: 16 completed an open-label, sequential 2-way crossover, 2-arm (randomized to ketoconazole and rifampicin) CYP3A study; another 18 participated in a double-blind, placebo-controlled, randomized 3-way crossover ethanol study. Administration of piragliatin (100-mg single dose) resulted in a 32% Cmax and 44% area under the curve (AUC∞ ) increase in piragliatin exposure without affecting glucose AUC0-6h following ketoconazole (400 mg QD × 5 days); 30% Cmax and 72% AUC∞ decrease in piragliatin exposure with a 13% increase in glucose AUC0-6h following rifampicin (600 mg QD × 5 days); and, unexpectedly, a 32% Cmax and 23% AUC0-6h decrease (no change in AUC∞ ) in piragliatin exposure with a 13% increase in glucose AUC0-6h following alcohol (40-g single dose). In conclusion, a strong CYP3A modifier or concomitant alcohol could lead to a change in exposure to piragliatin with a potential alteration in glucose-lowering effect.
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Pharmacokinetic interaction between the CYP3A4 inhibitor ketoconazole and the hormone drospirenone in combination with ethinylestradiol or estradiol.
Wiesinger, H, Berse, M, Klein, S, Gschwend, S, Höchel, J, Zollmann, FS, Schütt, B
British journal of clinical pharmacology. 2015;(6):1399-410
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Abstract
AIMS: The present study was conducted to investigate the influence of the strong CYP3A4 inhibitor ketoconazole (KTZ) on the pharmacokinetics of drospirenone (DRSP) administered in combination with ethinylestradiol (EE) or estradiol (E2). METHODS This was a randomized, multicentre, open label, one way crossover, fixed sequence study with two parallel treatment arms. A group sequential design allowed terminating the study for futility after first study cohort. About 50 healthy young women were randomized 1 : 1 to 'DRSP/EE' or 'DRSP/E2'. Subjects in the 'DRSP/EE' group received DRSP 3 mg/EE 0.02 mg (YAZ®, Bayer) once daily for 21 to 28 days followed by DRSP 3 mg/EE 0.02 mg once daily plus KTZ 200 mg twice daily for 10 days. Subjects in the 'DRSP/E2' group received DRSP 3 mg/E2 1.5 mg (research combination) once daily for 21 to 28 days followed by DRSP 3 mg/E2 1.5 mg once daily plus KTZ 200 mg twice daily for 10 days. RESULTS Oral co-administration of DRSP/EE or DRSP/E2 and KTZ resulted in an increase in DRSP exposure (AUC(0,24 h)) in both treatment groups: DRSP/EE group: 2.68-fold DRSP increase (90% CI 2.44, 2.95); DRSP/E2 group: 2.30-fold DRSP increase (90% CI 2.08, 2.54). EE and estrone (metabolite of E2) exposures were increased ~1.4-fold whereas E2 exposure was largely unaffected by KTZ co-administration. CONCLUSIONS A moderate pharmacokinetic drug-drug interaction between DRSP and KTZ was demonstrated in this study. No relevant changes of medical concern were detected in the safety data collected in this study.
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Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib.
Suttle, AB, Grossmann, KF, Ouellet, D, Richards-Peterson, LE, Aktan, G, Gordon, MS, LoRusso, PM, Infante, JR, Sharma, S, Kendra, K, et al
Journal of clinical pharmacology. 2015;(4):392-400
Abstract
The induction of CYP2C9 by dabrafenib using S-warfarin as a probe and the effects of a CYP3A inhibitor (ketoconazole) and a CYP2C8 inhibitor (gemfibrozil) on dabrafenib pharmacokinetics were evaluated in patients with BRAF V600 mutation-positive tumors. Dabrafenib single- and repeat-dose pharmacokinetics were also evaluated. S-warfarin AUC(0- ∞) decreased 37% and Cmax increased 18% with dabrafenib. Dabrafenib AUC(0- τ) and C(max) increased 71% and 33%, respectively, with ketoconazole. Hydroxy- and desmethyl-dabrafenib AUC(0-τ) increased 82% and 68%, respectively, and AUC for carboxy-dabrafenib decreased 16%. Dabrafenib AUC(0-τ) increased 47%, with no change in C(max), after gemfibrozil co-administration. Gemfibrozil did not affect systemic exposure to dabrafenib metabolites. Single- and repeat-dose dabrafenib pharmacokinetics were consistent with previous reports. All cohorts used the commercial capsules. More-frequent monitoring of international normalized ratios is recommended in patients receiving warfarin during initiation or discontinuation of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A or CYP2C8 is recommended during treatment with dabrafenib.
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Pasireotide alone or with cabergoline and ketoconazole in Cushing's disease.
Feelders, RA, de Bruin, C, Pereira, AM, Romijn, JA, Netea-Maier, RT, Hermus, AR, Zelissen, PM, van Heerebeek, R, de Jong, FH, van der Lely, AJ, et al
The New England journal of medicine. 2010;(19):1846-8
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Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer.
Taplin, ME, Regan, MM, Ko, YJ, Bubley, GJ, Duggan, SE, Werner, L, Beer, TM, Ryan, CW, Mathew, P, Tu, SM, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2009;(22):7099-105
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Abstract
PURPOSE Increasing evidence indicates that enhanced intratumoral androgen synthesis contributes to prostate cancer progression after androgen deprivation therapy. This phase II study was designed to assess responses to blocking multiple steps in androgen synthesis with inhibitors of CYP17A1 (ketoconazole) and type I and II 5alpha-reductases (dutasteride) in patients with castration-resistant prostate cancer (CRPC). EXPERIMENTAL DESIGN Fifty-seven men with CRPC were continued on gonadal suppression and treated with ketoconazole (400 mg thrice daily), hydrocortisone (30 mg/AM, 10 mg/PM), and dutasteride (0.5 mg/d). RESULTS Prostate-specific antigen response rate (> or =50% decline) was 56% (32 of 57; 95% confidence interval, 42.4-69.3%); the median duration of response was 20 months. In patients with measurable disease, 6 of 20 (30%) responded by the Response Evaluation Criteria in Solid Tumors. Median duration of treatment was 8 months; 9 patients remained on therapy with treatment durations censored at 18 to 32 months. Median time to progression was 14.5 months. Grade 3 toxicities occurred in 32% with only one reported grade 4 (thrombosis) toxicity. Dehydroepiandrosterone sulfate declined by 89%, androstenedione by 56%, and testosterone by 66%, and dihydrotestosterone declined to below detectable levels compared with baseline levels with testicular suppression alone. Median baseline levels and declines in dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were not statistically different in the responders versus nonresponders, and hormone levels were not significantly increased from nadir levels at relapse. CONCLUSION The response proportion to ketoconazole, hydrocortisone, and dutasteride was at least comparable with previous studies of ketoconazole alone, whereas time to progression was substantially longer. Combination therapies targeting multiple steps in androgen synthesis warrant further investigation.
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Effects of cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine pharmacokinetics.
Grimm, SW, Richtand, NM, Winter, HR, Stams, KR, Reele, SB
British journal of clinical pharmacology. 2006;(1):58-69
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Abstract
AIMS: To explore the potential for drug interactions on quetiapine pharmacokinetics using in vitro and in vivo assessments. METHODS The CYP enzymes responsible for quetiapine metabolite formation were assessed using recombinant expressed CYPs and CYP-selective inhibitors. P-glycoprotein (Pgp) transport was tested in MDCK cells expressing the human MDR1 gene. The effects of CYP3A4 inhibition were evaluated clinically in 12 healthy volunteers that received 25 mg quetiapine before and after 4 days of treatment with ketoconazole 200 mg daily. To assess CYP3A4 induction in vivo, 18 patients with psychiatric disorders were titrated to steady-state quetiapine levels (300 mg twice daily), then titrated to 600 mg daily carbamazepine for 2 weeks. RESULTS CYP3A4 was found to be responsible for formation of quetiapine sulfoxide and N- and O-desalkylquetiapine and not a Pgp substrate. In the clinical studies, ketoconazole increased mean quetiapine plasma C(max) by 3.35-fold, from 45 to 150 ng ml(-1) (mean C(max) ratio 90% CI 2.51, 4.47) and decreased its clearance (Cl/F) by 84%, from 138 to 22 l h(-1) (mean ratio 90% CI 0.13, 0.20). Carbamazepine decreased quetiapine plasma C(max) by 80%, from 1042 to 205 ng ml(-1) (mean C(max) ratio 90% CI 0.14, 0.28) and increased its clearance 7.5-fold, from 65 to 483 l h(-1) (mean ratio 90% CI 6.04, 9.28). CONCLUSIONS Cytochrome P450 3A4 is a primary enzyme responsible for the metabolic clearance of quetiapine. Quetiapine pharmacokinetics were affected by concomitant administration of ketoconazole and carbamazepine, and therefore other drugs and ingested natural products that strongly modulate the activity or expression of CYP3A4 would be predicted to change exposure to quetiapine.
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Effect of ketoconazole on the pharmacokinetics and safety of telithromycin and clarithromycin in older subjects with renal impairment.
Shi, J, Chapel, S, Montay, G, Hardy, P, Barrett, JS, Sica, D, Swan, SK, Noveck, R, Leroy, B, Bhargava, VO
International journal of clinical pharmacology and therapeutics. 2005;(3):123-33
Abstract
OBJECTIVE The objective of this study was to determine the effect of multiple impairments in drug elimination on the pharmacokinetics and pharmacodynamics (effect on QTc interval), using clarithromycin as a comparator. METHODS Thirty-two subjects aged > or = 60 years with renal impairment who were otherwise medically stable were recruited into this parallel-group study. Following stratification according to creatinine clearance (CL(CR)), subjects were randomized to a five-day treatment with ketoconazole (400 mg once daily) alone, or a five-day treatment with ketoconazole (400 mg once daily) and telithromycin (800 mg once daily) given concomitantly or a five-day treatment with ketoconazole (400 mg once daily) and clarithromycin (500 mg twice daily) given concomitantly. Steady-state pharmacokinetics and safety, including serial electrocardiograms, were assessed. RESULTS In subjects with CL(CR) 30 - 80 ml/min, the mean maximal telithromycin concentration at steady state (C(max),ss) was 3.6 mg/l and the steady state area under the plasma concentration-time curve from time zero to 24 hours (AUC(0-24 h) ss) was 33.4 mg x h/l. The mean C(max), ss and AUC(0-12 h)ss for clarithromycin were 6.2 mg/l and 56.1 mg x h/l, respectively. The increases in telithromycin C(max) ss and AUC(0-24 h) ss compared to corresponding data for healthy young subjects were 1.6- and 2.7-fold, respectively, whereas corresponding increases for clarithromycin were 2.2- and 3.3-fold, respectively. In the telithromycin plus ketoconazole group deltaQTc values were equal or < 60 ms. All QTc values were equal or < 450 ms in males and equal or < 470 ms in females. CONCLUSIONS The increase in telithromycin plasma concentrations during ketoconazole-mediated inhibition of CYP3A4 in subjects aged 60 years or older with renal impairment was similar to that for clarithromycin under the same conditions. Telithromycin was well tolerated and produced no clinically significant prolongations in the QTc interval.
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The interaction of saquinavir (soft gelatin capsule) with ketoconazole, erythromycin and rifampicin: comparison of the effect in healthy volunteers and in HIV-infected patients.
Grub, S, Bryson, H, Goggin, T, Lüdin, E, Jorga, K
European journal of clinical pharmacology. 2001;(2):115-21
Abstract
OBJECTIVE The aim of this study was to compare the effect of ketoconazole, erythromycin and rifampicin on the pharmacokinetics of saquinavir soft-gelatin formulation (Fortovase; FTV) in healthy volunteers with that in HIV-infected patients at steady state after administration of 1200 mg three times daily. METHODS In two open-labelled, randomised, crossover studies pharmacokinetic parameters were calculated in healthy volunteers who received on one occasion multiple doses of 1200 mg FTV three times daily alone and on the other occasion in combination with multiple doses of either 400 mg ketoconazole once daily or 600 mg rifampicin once daily. In another open-labelled, multicentre study, 33 HIV-infected patients underwent a pharmacokinetic assessment after 36-51 weeks of treatment with FTV and were then given additionally multiple doses of either 200 mg ketoconazole once daily, 250 mg erythromycin four times daily or 600 mg rifampicin once daily. Pharmacokinetic parameters of saquinavir were determined again at the end of the combination treatment. RESULTS In healthy volunteers, coadministration of ketoconazole increased saquinavir area under the curve from time 0 to 8 h (AUC0-8 h) by 190% (95% CI: 90-343) whereas coadministration with rifampicin resulted in a decrease for AUC0-8 h by 70% (95% CI: 50-82). In HIV-infected patients, coadministration of ketoconazole and erythromycin increased AUC0-8 h of saquinavir by 69% (95% CI: 14-150) and 99% (95% CI: 33-198), respectively. When saquinavir was given together with rifampicin, exposure of saquinavir in terms of AUC0-8 h was decreased by 46% (95% CI: 18-65) compared with the baseline assessment. CONCLUSION Interactions of saquinavir with ketoconazole, erythromycin and rifampicin were observed in healthy volunteers as well as patients. The effects observed in patients, however, appear to be less pronounced. The enzyme induction caused by rifampicin might lead to subtherapeutic levels of saquinavir and this finding appears to be of clinical relevance.