Dataset Information

Rilpivirine Pharmacokinetics Without and With Darunavir/Ritonavir Once Daily in Adolescents and Young Adults.

ABSTRACT: Rilpivirine (RPV), a recently developed, once daily human immunodeficiency virus non-nucleoside reverse transcriptase inhibitor, is not currently approved for pediatric patients, but is sometimes prescribed for adolescents with multiple treatment failures, for regimen simplification or to minimize toxicity. Darunavir/ritonavir (DRV/r) administered once daily is also increasingly used in adolescents and may alter RPV pharmacokinetics (PK). We evaluated the PK interactions between RPV and DRV/r once daily in adolescents and young adults.Human immunodeficiency virus-infected subjects 12 to <24 years old receiving a stable background therapy including RPV 25?mg once daily without or combined with DRV/r 800/100?mg once daily were enrolled. Intensive 24-hour blood sampling was performed, and PK indices were determined using noncompartmental analysis. Protocol-defined target drug exposure ranges based on adult data were used to assess the adequacy of each regimen.Fifteen subjects receiving RPV without and 14 subjects with DRV/r were enrolled. When dosed without DRV/r, the RPV geometric mean (90% confidence interval) for RPV AUC0-24, Cmax and C24 h were 2.38 ?g h/mL (1.92-2.94), 0.14 ?g/mL (0.12-0.18) and 0.07 ?g/mL (0.03-0.10), respectively, similar to adult values. RPV concentrations were significantly increased with concomitant DRV/r use: RPV AUC24, Cmax and C24 h were 6.74 ?g h/mL (4.89-9.28), 0.39 ?g/mL (0.27-0.57) and 0.23 ?g/mL (0.17-0.32), respectively, well above the target ranges based on adult data. DRV/r PK was not affected by coadministration of RPV.RPV PK in this adolescent population was similar to adults when dosed without DRV/r. DRV/r coadministration increased RPV exposure 2- to 3-fold, indicating that drug-related side effects should be closely monitored.

SUBMITTER: Foca M

PROVIDER: S-EPMC5245132 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Rilpivirine Pharmacokinetics Without and With Darunavir/Ritonavir Once Daily in Adolescents and Young Adults.

Foca Marc M Yogev Ram R Wiznia Andrew A Hazra Rohan R Jean-Philippe Patrick P Graham Bobbie B Britto Paula P Carey Vincent J VJ King Jennifer J Acosta Edward P EP Cressey Tim R TR

The Pediatric infectious disease journal 20160901 9

<h4>Background</h4>Rilpivirine (RPV), a recently developed, once daily human immunodeficiency virus non-nucleoside reverse transcriptase inhibitor, is not currently approved for pediatric patients, but is sometimes prescribed for adolescents with multiple treatment failures, for regimen simplification or to minimize toxicity. Darunavir/ritonavir (DRV/r) administered once daily is also increasingly used in adolescents and may alter RPV pharmacokinetics (PK). We evaluated the PK interactions betwe ...[more]

PMID: 27187753

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Project description:The object of this study was to investigate the pharmacokinetics of darunavir-ritonavir and atazanavir-ritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavir-ritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0- to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0- to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC(50)] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the protein-binding-corrected IC(50) for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval of 24 h which were above the cutoff used to define therapeutic concentrations.

Project description:Pregnant women are usually excluded from clinical trials. Physiologically based pharmacokinetic (PBPK) modelling may provide a method to predict pharmacokinetics in pregnant women, without the need to perform extensive in vivo clinical trials. Here, we used mechanistic modelling to delineate the potential impact of drug transporters on darunavir pharmacokinetics and to identify current knowledge gaps that limit accurate PBPK modelling of darunavir/ritonavir (darunavir/r) exposure in pregnancy. Simcyp (version 13.2) was used for PBPK modelling, using physicochemical and in vitro pharmacokinetic parameters of darunavir and ritonavir from the literature. The Michaelis-Menten constant (K m) and the maximum rate of metabolite formation (V max) for cytochrome P450 3A4-mediated darunavir biotransformation and inhibition by ritonavir were determined experimentally, while the contributions of hepatocyte influx and efflux transporters were assessed by sensitivity analysis. The simulations were compared with previously published clinical pharmacokinetic data. We found that use of a well-stirred liver model overestimated darunavir exposure substantially. A permeability-limited liver model, including hepatic uptake and efflux transporters and an efficient enterohepatic circulation step, resulted in an acceptable description of darunavir/r exposure. For the 600/100 mg darunavir/r twice-daily dose and the 800/100 mg once-daily dose, the estimated pharmacokinetic parameters were within a 2-fold range of the reported data. The predicted decreases in the area under the concentration-time curve (AUC) values during pregnancy for the twice- and once-daily doses were 27 and 41%, respectively, which were in line with the observed decreases of 17-22 and 33%. In conclusion, our data support a clinically relevant role of hepatic transporters in darunavir pharmacokinetics. By including them in our model, we successfully approximated the increase in darunavir exposure mediated by ritonavir co-administration and the decrease in darunavir exposure observed during pregnancy.

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Dataset Information

Rilpivirine Pharmacokinetics Without and With Darunavir/Ritonavir Once Daily in Adolescents and Young Adults.

Publications

Rilpivirine Pharmacokinetics Without and With Darunavir/Ritonavir Once Daily in Adolescents and Young Adults.

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