Tafenoquine at therapeutic concentrations does not prolong Fridericia-corrected QT interval in healthy subjects.

Tafenoquine is being developed for relapse prevention in Plasmodium vivax malaria. This Phase I, single-blind, randomized, placebo- and active-controlled parallel group study investigated whether tafenoquine at supratherapeutic and therapeutic concentrations prolonged cardiac repolarization in healthy volunteers. Subjects aged 18-65 years were randomized to one of five treatment groups (n = 52 per group) to receive placebo, tafenoquine 300, 600, or 1200 mg, or moxifloxacin 400 mg (positive control). Lack of effect was demonstrated if the upper 90% CI of the change from baseline in QTcF following supratherapeutic tafenoquine 1200 mg versus placebo (ΔΔQTcF) was <10 milliseconds for all pre-defined time points. The maximum ΔΔQTcF with tafenoquine 1200 mg (n = 50) was 6.39 milliseconds (90% CI 2.85, 9.94) at 72 hours post-final dose; that is, lack of effect for prolongation of cardiac depolarization was demonstrated. Tafenoquine 300 mg (n = 48) or 600 mg (n = 52) had no effect on ΔΔQTcF. Pharmacokinetic/pharmacodynamic modeling of the tafenoquine-QTcF concentration-effect relationship demonstrated a shallow slope (0.5 ms/µg mL(-1) ) over a wide concentration range. For moxifloxacin (n = 51), maximum ΔΔQTcF was 8.52 milliseconds (90% CI 5.00, 12.04), demonstrating assay sensitivity. In this thorough QT/QTc study, tafenoquine did not have a clinically meaningful effect on cardiac repolarization.

Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects.

AIMS: The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. METHODS: Healthy subjects, 18-55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1-2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days. RESULTS: The coadministration of CQ + TQ had no effect on TQ AUC0-t , AUC0-∞ , Tmax or t1/2 . The 90% confidence intervals of CQ + TQ vs. TQ for AUC0-t , AUC0-∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0-24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated. CONCLUSIONS: No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects.

Pharmacokinetics of oral sitamaquine taken with or without food and safety and efficacy for treatment of visceral leishmaniais: a randomized study in Bihar, India.

This randomized, open-label study of patients in India with visceral leishmaniasis (VL) investigated the effect of food on sitamaquine and desethyl-sitamaquine pharmacokinetics. Patients were randomized to receive oral sitamaquine, 2 mg/kg/day, once a day for 21 days across four cohorts (n = 41) (fasted/fed, fed/fasted, fed/fed, and fasted/fasted) over two periods (days 1-10 and 11-21), or intravenous amphotericin B (AmB), 1 mg/kg every other day for 30 days (n = 20). Mean day 21 pharmacokinetics across the four cohorts were sitamaquine, area under curve (AUC)((0-τ)) = 6,627-8,903 ng.hr/mL, AUC((0-16)) = 4,859-6,633 ng.hr/mL, maximum plasma concentration (C(max)) = 401-570 ng/mL, apparent terminal half-life (t(1/2)) = 18.3-22.8 hr, time to reach C(max) (t(max)) = 3.5-6 hr; and desethyl-sitamaquine, AUC((0-τ)) = 2,307-3,163 ng.hr/mL, C(max) = 109-154 ng/mL, t(1/2) = 23.0-27.9 hr, t(max) = 2-10 hr, with no significant food effect. On-therapy adverse events were observed for sitamaquine in 4 (10%) of 41 patients and for AmB in 17 (85%) of 20 patients. The final clinical cure (day 180) was 85% (95% confidence interval = 70.8-94.4%) for sitamaquine and 95% (95% confidence interval = 75.1-99.9) for AmB. Sitamaquine can be taken regardless of food intake, was generally well tolerated, and showed potential efficacy in patients with visceral leishmaniasis.

Effects of genetic variation at the CYP2C19/CYP2C9 locus on pharmacokinetics of chlorcycloguanil in adult Gambians.

AIMS: Antimalarial biguanides are metabolized by CYP2C19, thus genetic variation at the CYP2C locus might affect pharmacokinetics and so treatment outcome for malaria. MATERIALS & METHODS: Polymorphisms in CYP2C19 and CYP2C9 in 43 adult Gambians treated with chlorproguanil/dapsone for uncomplicated malaria were assessed. Chlorcycloguanil pharmacokinetics were measured and associations with CYP2C19 and CYP2C9 alleles and CYP2C19 metabolizer groups investigated. RESULTS: All CYP2C19/CYP2C9 alleles obeyed Hardy-Weinberg equilibrium. There were 15 CYP2C19/2C9 haplotypes with a common haplotype frequency of 0.23. Participants with the CYP2C19*17 allele had higher chlorcycloguanil area under the concentration versus curve at 24 h (AUC(0-24)) than those without (geometric means: 317 vs 216 ng.h/ml; ratio of geometric means: 1.46; 95% CI: 1.03 to 2.09; p = 0.0363) and higher C(max) (geometric mean ratio: 1.52; 95% CI: 1.13 to 2.05; p = 0.0071). CONCLUSION: CYP2C19*17 determines antimalarial biguanide metabolic profile at the CYP2C19/CYP2C9 locus.

Pharmacokinetics of chlorproguanil, dapsone, artesunate and their major metabolites in patients during treatment of acute uncomplicated Plasmodium falciparum malaria.

OBJECTIVE: Chlorproguanil (CPG)-dapsone (DDS)-artesunate was in development for the treatment of uncomplicated Plasmodium falciparum malaria. The pharmacokinetics of CPG, DDS, artesunate and their metabolites chlorcycloguanil (CCG), monoacetyl dapsone (MADDS) and dihydroartemisinin (DHA) were investigated in patients with P. falciparum given CPG-DDS alone or plus artesunate. METHODS: Adult patients from Malawi and The Gambia taking part in a phase II clinical trial were randomised to receive a 3-day treatment of CPG-DDS alone (2/2.5 mg/kg/day) or plus 1, 2 or 4 mg/kg/day artesunate. Blood samples for pharmacokinetic analysis were collected up to 24 h post-first dose. RESULTS: The pharmacokinetic analysis included 115 patients. For CPG, there was no significant effect of artesunate on C(max) or AUC(0-24), except the 90% confidence interval (CI) for AUC(0-24) for the 4 mg/kg artesunate dose was slightly below that for the standard bioequivalence range (90% CI 0.78, 1.11); this was not considered clinically relevant. Artesunate increased the CCG AUC(0-24) by 6-17% and C(max) by 0-16%. Artesunate had no significant effect on the rate or extent of absorption of DDS. For MADDS, artesunate increased the AUC(0-24) by 13-47% and C(max) by 8-45%. For 1, 2 and 4 mg/kg artesunate dosing, artesunate AUC(0-infinity) was 64.6, 151 and 400 ng.h/ml and C(max) 48.9, 106 and 224 ng/ml respectively; DHA AUC(0-infinity) was 538, 1,445 and 3,837 ng.h/ml and C(max) 228, 581 and 1,414 ng/ml respectively. Using a power model, the point estimates of slope were greater than 1 for artesunate AUC(0-t) by 16% and C(max) by 5% and for DHA by 39 and 21% respectively. CONCLUSION: Artesunate did not significantly affect CPG or DDS pharmacokinetics. For CCG and MADDS, small to moderate increases in exposure with artesunate dosing were observed. There was a greater than proportional increase in artesunate and DHA exposure with increasing artesunate dose. These effects are not considered to be clinically relevant. It should be noted that the CPG-DDS-artesunate programme has now been stopped following unacceptable haematological toxicity in patients with glucose-6-phosphate dehydrogenase deficiency during a phase III trial. In addition, the CPG-DDS combination has been withdrawn from clinical use.

Population pharmacokinetics of tafenoquine during malaria prophylaxis in healthy subjects.

The population pharmacokinetics of tafenoquine were studied in Australian soldiers taking tafenoquine for malarial prophylaxis. The subjects (476 males and 14 females) received a loading dose of 200 mg tafenoquine base daily for 3 days, followed by a weekly dose of 200 mg tafenoquine for 6 months. Blood samples were collected from each subject after the last loading dose and then at weeks 4, 8, and 16. Plasma tafenoquine concentrations were determined by liquid chromatography-tandem mass spectrometry. Population modeling was performed with NONMEM, using a one-compartment model. Typical values of the first-order absorption rate constant (K(a)), clearance (CL/F), and volume of distribution (V/F) were 0.243 h(-1), 0.056 liters/h/kg, and 23.7 liters/kg, respectively. The intersubject variability (coefficient of variation) in CL/F and V/F was 18% and 22%, respectively. The interoccasion variability in CL/F was 18%, and the mean elimination half-life was 12.7 days. A positive linear association between weight and both CL/F and V/F was found, but this had insufficient impact to warrant dosage adjustments. Model robustness was assessed by a nonparametric bootstrap (200 samples). A degenerate visual predictive check indicated that the raw data mirrored the postdose concentration-time profiles simulated (n = 1,000) from the final model. Individual pharmacokinetic estimates for tafenoquine did not predict the prophylactic outcome with the drug for four subjects who relapsed with Plasmodium vivax malaria, as they had similar pharmacokinetics to those who were free of malaria infection. No obvious pattern existed between the plasma tafenoquine concentration and the pharmacokinetic parameter values for subjects with and without drug-associated moderate or severe adverse events. This validated population pharmacokinetic model satisfactorily describes the disposition and variability of tafenoquine used for long-term malaria prophylaxis in a large cohort of soldiers on military deployment.

Pharmacokinetics of rosiglitazone in patients with varying degrees of renal insufficiency.

This study investigated the effect of varying degrees of renal insufficiency on the pharmacokinetics of rosiglitazone. Subjects were stratified by estimated creatinine clearance: normal (> 80 mL/min; n = 12), mild renal insufficiency (60-80 mL/min; n = 15), moderate renal insufficiency (30-59 mL/min; n = 18), and severe renal insufficiency not requiring dialysis (< or = 29 mL/min; n = 12). Plasma rosiglitazone concentrations and protein binding were determined after a single oral 8-mg dose of rosiglitazone. Total and unbound pharmacokinetic parameters were generated using noncompartmental methods. AUC, Cmax, and t1/2 data were analyzed separately by ANOVA to provide point estimates and corresponding 95% confidence intervals. The pharmacokinetics of rosiglitazone was not markedly affected by mild, moderate, or severe renal insufficiency. Slight increases (approximately 10%-20%) in mean unbound AUC0-infinity values were observed for each insufficiency group compared to the normal group but were not considered to be clinically relevant. Patients with severe insufficiency exhibited a 38% increase in mean fraction unbound, leading to an increase in total clearance, which resulted in a 19% to 24% lower mean total AUC0-infinity and Cmax values relative to the normal group. The rates of mild or moderate adverse events were similar for all groups; there were no severe adverse events. Impaired renal function does not markedly alter the pharmacokinetics of total or unbound rosiglitazone following a single dose of rosiglitazone. Therefore, the starting dose of rosiglitazone does not need to be adjusted in patients with renal impairment. Subsequent dose adjustments should be based on individual patient response.

The effect of ranitidine on the pharmacokinetics of rosiglitazone in healthy adult male volunteers.

BACKGROUND: Rosiglitazone is an insulin-sensitizing oral agent in the thiazolidinedione class used to treat patients with type 2 diabetes mellitus. It binds to peroxisome proliferator-activated receptor gamma in liver, muscle, and adipose tissue. Ranitidine, a histamine2-receptor antagonist, may be prescribed for patients with type 2 diabetes and esophageal symptoms such as heartburn. By raising gastrointestinal pH levels, ranitidine may affect the bioavailability of coadministered drugs. OBJECTIVES: This article presents the absolute bioavailability of rosiglitazone, as well as the effects of ranitidine on the pharmacokinetics of rosiglitazone. METHODS: Healthy men were enrolled in a randomized, open-label, 4-period, period-balanced crossover study of rosiglitazone and ranitidine. All individuals received each of 4 regimens successively, separated by a 4-day washout period: a single IV dose of rosiglitazone 2 mg administered alone over 1 hour; a single IV dose of rosiglitazone 2 mg administered over 1 hour on the fourth day of treatment with oral ranitidine 150 mg given every 12 hours; a single oral dose of rosiglitazone 4 mg alone; and a single oral dose of rosiglitazone 4 mg on the fourth day of treatment with oral ranitidine 150 mg given every 12 hours. The primary end point was dose-normalized area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)). Maximum observed plasma concentration (Cmax), the time at which Cmax occurred (Tmax), plasma clearance (CL), steady-state volume of distribution (Vss), and terminal elimination half-life (t 1/2) were also assessed. RESULTS: Twelve individuals were enrolled. The absolute bioavailability of rosiglitazone was 99%. For AUC(0-infinity), the point estimate and the associated 95% CI for the ratio of ranitidine + IV rosiglitazone to IV rosiglitazone alone was 1.02 (range, 0.88-1.20). With oral rosiglitazone, the AUC(0-infinity) point estimate (95% CI) for the ratio of ranitidine + rosiglitazone to rosiglitazone alone was 0.99 (range, 0.85-1.16). Cmax, Tmax, t 1/2, Vss and CL of rosiglitazone, whether administered orally or intravenously, were unaffected by ranitidine. Oral and IV rosiglitazone were associated with a favorable safety profile and were well tolerated with or without concurrent ranitidine treatment. CONCLUSIONS: In this study of 12 healthy adult male volunteers, the absolute bioavailability of rosiglitazone was 99%, and the oral and IV single-dose pharmacokinetics of rosiglitazone were unaltered by concurrent treatment with ranitidine.