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Pharmacokinetics and tolerability of oseltamivir combined with probenecid.

ABSTRACT: Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days. Pharmacokinetic data, obtained by noncompartmental methods, and safety data are reported. Forty-eight subjects completed the pharmacokinetic analysis. The study drugs were generally well tolerated, except for one case of reversible grade 4 thrombocytopenia in a subject in group 2. The calculated 90% confidence intervals (CIs) for the geometric mean ratios between groups 2 and 3 and group 1 were outside the bioequivalence criteria boundary (0.80 to 1.25) at 0.63 to 0.89 for group 2 versus group 1 and 0.57 to 0.90 for group 3 versus group 1. The steady-state apparent oral clearance of oseltamivir carboxylate was significantly less in groups 2 (7.4 liters/h; 90% CI, 6.08 to 8.71) and 3 (7.19 liters/h; 90% CI, 6.41 to 7.98) than in group 1 (9.75 liters/h; 90% CI, 6.91 to 12.60) (P < 0.05 for both comparisons by analysis of variance). The (arithmetic) mean concentration at 48 h for group 2 was not significantly different from the mean concentration at 24 h for group 1 (42 +/- 76 and 81 +/- 54 ng/ml, respectively; P = 0.194), but the mean concentration at 48 h for group 3 was significantly less than the mean concentration at 24 h for group 1 (23 +/- 26 and 81 +/- 54 ng/ml, respectively; P = 0.012). Alternate-day dosing of oseltamivir plus dosing with probenecid four times daily achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro, and this combination should be studied further.

SUBMITTER: Holodniy M

PROVIDER: S-EPMC2533494 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Pharmacokinetics and tolerability of oseltamivir combined with probenecid.

Holodniy Mark M Penzak Scott R SR Straight Timothy M TM Davey Richard T RT Lee Kelvin K KK Goetz Matthew Bidwell MB Raisch Dennis W DW Cunningham Francesca F Lin Emil T ET Olivo Noemi N Deyton Lawrence R LR

Antimicrobial agents and chemotherapy 20080616 9

Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg ...[more]

PMID: 18559644

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Project description:BackgroundOlmesartan is an angiotensin II receptor antagonist and is effective and well tolerated in the treatment of arterial hypertension. Probenecid is a well-established hypouricemic agent for the treatment of hyperuricemia and gout.ObjectiveThe goal of this study was to examine the impact of coadministration of probenecid on the pharmacokinetic parameters and tolerability of olmesartan in healthy volunteers.MethodsIn a randomized, open-label, 2-way crossover study, 12 volunteers received 2 oral treatments (olmesartan alone or olmesartan plus probenecid) separated by 4 days. Blood samples were obtained for a 48-hour pharmacokinetic evaluation after drug administration. Tolerability was assessed by monitoring vital signs and laboratory tests before and after administration of the study drug.ResultsPharmacokinetic parameters were evaluated in 6 male and 6 female healthy volunteers (mean age, 22 [range, 20-25] years]; weight, 56.0 [range, 51.0-60.0] kg). Probenecid coadministration increased olmesartan Css-av, AUC0→∞, and AUC0-48 by 40%, 50%, and 50%, respectively (P = 0.018, 0.000, 0.000, respectively), but there was no statistical significance for Tmax, t1/2, Css-max, and Css-min between olmesartan plus probenecid and olmesartan alone (P = 0.697, 0.053, 0.521, and 0.734, respectively). No serious adverse event (AE) was reported during the study. The proportion of volunteers with AEs in the olmesartan plus probenecid period (5 of 12 [42%]) was higher than that in the olmesartan-alone period (1 of 12 [8%]). All of the AEs during the olmesartan plus probenecid period were abnormal routine urine test results. The AE in olmesartan-alone period was dizziness. All AEs were classified as mild and considered to be at least possibly related to treatment. All volunteers recovered from the AEs by 2 weeks after the end of the study.ConclusionsProbenecid increases the exposure speed of olmesartan by increasing the AUC0-48, AUC0→∞, and Css-av. The combined treatment of olmesartan medoxomil with probenecid may increase the occurrence of genitourinary side effects. ClinicalTrials.gov identifier: NCT01907373.

Project description:PurposeThis study aimed to characterize the pharmacokinetic (PK) properties, safety, and tolerability of asenapine, and to develop a population PK model in pediatric patients with schizophrenia, bipolar disorder, or other psychiatric disorders.MethodsTwo Phase I multiple ascending-dose studies were conducted to evaluate the PK, safety, and tolerability of sublingual asenapine in pediatric patients (age 10-17 years) with schizophrenia or bipolar I disorder. Patients received asenapine 1-10 mg twice daily for up to 12 days. PK parameters (maximum concentration [Cmax], area under the curve from 0 to 12 hours [AUC0-12], time to Cmax [Tmax], and half-life) were summarized for asenapine with descriptive statistics, and safety parameters were collected. A population PK model, which included the two Phase I studies and two additional Phase III efficacy studies (asenapine 2.5-10 mg twice daily for up to 8 weeks, age 10-17 years), was developed using nonlinear mixed-effect modeling based on a previously developed adult PK model. The final model was used in simulations to obtain asenapine-exposure estimates across pediatric subgroups and to determine if intrinsic covariates warrant dose adjustments.ResultsThe PK of asenapine showed rapid absorption (Tmax ~1 hour) with an apparent terminal half-life between 16 and 32 hours. Increases in mean Cmax and AUC0-12 appeared to be dose-proportional in one study and near dose-proportional in the second study. Steady state was attained within 8 days. The most frequently occurring treatment-emergent adverse events were dysgeusia, sedation, and oral hypoesthesia. Simulation-based estimates of Cmax and AUC0-12 were similar for pediatric and adult patients; age, body-mass index, race, and sex were not associated with changes in asenapine exposure.ConclusionAsenapine was generally safe and well tolerated in pediatric patients aged 10-17 years. PK and safety data were similar to that observed in the adult population. Intrinsic factors had no significant impact on asenapine exposure, indicating there is no need for dose adjustments in the pediatric population.

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Pharmacokinetics and tolerability of oseltamivir combined with probenecid.

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Pharmacokinetics and tolerability of oseltamivir combined with probenecid.

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