Klaus-Dieter Riedel

Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers

Ritonavir is a potent in vitro inhibitor of several cytochrome P450 isozymes and ABC transporters including the efflux pump P‐glycoprotein (P‐gp). This study assessed the effect of repetitive ritonavir administration on digoxin distribution and total and renal digoxin clearance as a marker for P‐gp activity in vivo.

Opposite effects of short‐term and long‐term St John's wort intake on voriconazole pharmacokinetics

Constituents of St Johns wort (SJW) in vivo induce the cytochrome P450 (CYP) isozymes 3A4, 2C9, and 2C19 but in vitro were shown to inhibit them. This study investigates both short‐ and long‐term effects of SJW on the antifungal voriconazole, which is metabolized by these enzymes.

Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir.

Cytochrome P450 (CYP) 2C19 and CYP3A4 are the major enzymes responsible for voriconazole elimination. Because the activity of CYP2C19 is under genetic control, the extent of inhibition with a CYP3A4 inhibitor was expected to be modulated by the CYP2C19 metabolizer status. This study thus assessed the effect of the potent CYP3A4 inhibitor ritonavir after short‐term administration on voriconazole pharmacokinetics in extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19.

Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Pharmacokinetic variability of voriconazole is largely caused by CYP3A4- and CYP2C19-mediated metabolism. * Oral bioavailability of voriconazole has been claimed to be almost 100%, thus facilitating a change from intravenous to oral application without dose adjustment. WHAT THIS STUDY ADDS * For the first time voriconazole exposure after intravenous and oral administration in relation to CYP2C19 activity is reported. * In addition, the predominant metabolic pathway is the hydroxylation that seems to be influenced by the CYP2C19 genotype. * Enterohepatic circulation of both hydroxylated metabolites must be anticipated. AIMS The aim was to determine the pharmacokinetics of voriconazole after a single oral dose in comparison with intravenous (i.v.) administration in healthy individuals stratified according to the cytochrome P450 (CYP) 2C19 genotype. In addition, the possible metabolic pathways and their modulation according to CYP2C19 genotype were investigated after oral and i.v. administration of voriconazole. METHODS In a single-centre, open-label, two-period crossover study 20 participants received single doses of 400 mg voriconazole orally and 400 mg voriconazole intravenously in randomized order. Blood and urine samples were collected up to 96 h post dose and the voriconazole and three major metabolites were quantified by high-performance liquid chromatography coupled to mass spectroscopy. RESULTS Absolute oral bioavailability of voriconazole was 82.6% (74.1, 91.0). It ranged from 94.4% (78.8, 109.9) in CYP2C19 poor metabolizers to 75.2% (62.9, 87.4) in extensive metabolizers. In contrast to voriconazole and its N-oxide, the plasma concentrations of both hydroxylated metabolites showed a large second peak after 24 h. Independent of the route of administration, voriconazole partial metabolic hydroxylation after i.v. administration was eightfold higher compared with N-oxidation [48.8 ml min(-1) (30.5, 67.1) vs. 6.1 ml min(-1) (4.1, 8.0)]. The formation of the metabolites was related to CYP2C19 activity. CONCLUSIONS Independent of the route of administration, voriconazole exposure was three times higher in CYP2C19 poor metabolizers compared with extensive metabolizers. Voriconazole has a high bioavailability with no large differences between the CYP2C19 genotypes. The hydroxylation pathway of voriconazole elimination exceeded the N-oxidation, both influenced by the CYP2C19 genotype.

Long‐Term Efavirenz Autoinduction and Its Effect on Plasma Exposure in HIV Patients

We investigated the influence of gender and pharmacogenetic variations on long‐term efavirenz autoinduction and disposition among patients with HIV in Tanzania (N = 129). Plasma concentrations (at 16 h) of efavirenz and 8‐hydroxyefavirenz were quantified at weeks 4 and 16 of therapy. Genotyping was performed to identify cytochrome P450 (CYP) 2B6*6, CYP3A5*3, *6, and *7, and ABCB1–3435 C/T genotypes. There were reductions in the median efavirenz concentration (Wilcoxon matched‐pair test P < 0.001) and efavirenz/8‐hydroxyefavirenz ratio (P < 0.001) by 19 and 32%, respectively, at week 16 as compared with week 4. The proportion of patients with efavirenz concentration <1 µg/ml at week 16 was higher by 67, 25, and 5% in CYP2B6*1/*1, *1/*6, and *6/*6 genotypes, respectively. The defined therapeutic range based on observed plasma concentrations is affected by the time point of sampling and the CYP2B6 genotype. The effect of efavirenz autoinduction on reducing plasma exposure continues up to week 16 and predominantly affects CYP2B6 extensive metabolizers. Among CYP2B6 slow metabolizers, the presence of a CYP3A5 genotype allele is associated with greater effects of efavirenz autoinduction on plasma concentrations of the drug. The cumulative induction may influence the long‐term antiretroviral therapy outcome, particularly in CYP2B6*1 carriers.

Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine

The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB) has a similar mode of action as chloroquine (CQ) and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso (CQ monotherapy had a > 50% clinical failure rate in this area in 2003). Three serious adverse events (SAE) occurred of which one was probably attributable to the study medication. In the per protocol safety analysis, there were no dose specific effects. The overall clinical and parasitological failure rates by day 14 were 10% [95% CI (7.5%, 14.0%)] and 24% [95% CI (19.4%, 28.3%)], respectively. MB appears to have efficacy against malaria, but the combination of CQ-MB is clearly not effective in the treatment of malaria in Africa.

Pharmacokinetic and pharmaceutic interaction between digoxin and Cremophor RH40

The pharmacokinetics of digoxin is modulated by the efflux pump P‐glycoprotein. Cremophor EL (BASF Aktiengesellschaft, Ludwigshafen, Germany) (polyoxyl 35 castor oil), a castor oil derivative used to improve the solubilization of drugs and vitamins, has been shown to inhibit this membrane transporter in vitro and in vivo. So far, no study in humans has evaluated the effect of Cremophor RH40 (BASF Aktiengesellschaft) (polyoxyl 40 hydrogenated castor oil) on P‐glycoprotein.

Importance of ethnicity, CYP2B6 and ABCB1 genotype for efavirenz pharmacokinetics and treatment outcomes: a parallel-group prospective cohort study in two sub-Saharan Africa populations.

Objectives We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations. Methods ART naïve HIV patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done. Result Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p = 0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART. Conclusion We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations.

Effect of rifampicin and CYP2B6 genotype on long-term efavirenz autoinduction and plasma exposure in HIV patients with or without tuberculosis.

We performed a prospective comparative study to examine, from a pharmacogenetics perspective, the effect of rifampicin (RIF) on long‐term efavirenz (EFV) autoinduction and kinetics. In a study population of patients with HIV receiving EFV with RIF (arm 2, n = 54) or without RIF (arm 1, n = 128 controls), intraindividual and interindividual plasma EFV and 8‐hydroxyefavirenz levels were compared at weeks 4 and 16 of EFV therapy. In arm 2, RIF was initiated 4 weeks before starting EFV. In controls (arm 1), the plasma EFV was significantly lower whereas 8‐hydroxyefavirenz was higher at week 16 as compared to week 4. By contrast, there were no significant differences in plasma EFV and 8‐hydroxyefavirenz concentrations over time in arm 2. At week 4, the plasma EFV concentration was significantly lower in arm 2 as compared to arm 1, but no significant differences were observed by week 16. When stratified by CYP2B6 genotype, significant differences were observed only with respect to CYP2B6*1/*1 genotypes. Ours is the first report of the CYP2B6 genotype‐dependent effect of RIF on long‐term EFV autoinduction.

Pharmacokinetics of Sulfobutylether-Beta-Cyclodextrin and Voriconazole in Patients with End-Stage Renal Failure during Treatment with Two Hemodialysis Systems and Hemodiafiltration

ABSTRACT Sulfobutylether-beta-cyclodextrin (SBECD), a large cyclic oligosaccharide that is used to solubilize voriconazole (VRC) for intravenous administration, is eliminated mainly by renal excretion. The pharmacokinetics of SBECD and voriconazole in patients undergoing extracorporeal renal replacement therapies are not well defined. We performed a three-period randomized crossover study of 15 patients with end-stage renal failure during 6-hour treatment with Genius dialysis, standard hemodialysis, or hemodiafiltration using a high-flux polysulfone membrane. At the start of renal replacement therapy, the patients received a single 2-h infusion of voriconazole (4 mg per kg of body weight) solubilized with SBECD. SBECD, voriconazole, and voriconazole-N-oxide concentrations were quantified in plasma and dialysate samples by high-performance liquid chromatography (HPLC) and by HPLC coupled to tandem mass spectrometry (LC-MS-MS) and analyzed by noncompartmental methods. Nonparametric repeated-measures analysis of variance (ANOVA) was used to analyze differences between treatment phases. SBECD and voriconazole recoveries in dialysate samples were 67% and 10% of the administered doses. SBECD concentrations declined with a half-life ranging from 2.6 ± 0.6 h (Genius dialysis) to 2.4 ± 0.9 h (hemodialysis) and 2.0 ± 0.6 h (hemodiafiltration) (P < 0.01 for Genius dialysis versus hemodiafiltration). Prediction of steady-state conditions indicated that even with daily hemodialysis, SBECD will still exceed SBECD exposure of patients with normal renal function by a factor of 6.2. SBECD was effectively eliminated during 6 h of renal replacement therapy by all methods, using high-flux polysulfone membranes, whereas elimination of voriconazole was quantitatively insignificant. The SBECD half-life during renal replacement therapy was nearly normalized, but the average SBECD exposure during repeated administration is expected to be still increased.