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Bioequivalence of a Fixed-Dose Combination Tablet of the Complete Two-Drug Regimen of Dolutegravir and Rilpivirine for Treatment of HIV-1 Infection.

ABSTRACT: A complete 2-drug regimen of dolutegravir at 50 mg and rilpivirine at 25 mg was approved to treat HIV-1 infection in virologically suppressed patients after demonstrating acceptable efficacy and tolerability. This study investigated the bioequivalence and pharmacokinetics of the fixed-dose combination tablet compared with those of separate tablets. Secondary endpoints were the tolerability and safety of the fixed-dose combination tablet. In this open-label, randomized-sequence, 2-way crossover trial, single doses of the fixed-dose combination tablet (the test treatment) and the combination of separate tablets (the reference treatment) were administered to healthy adults after a moderate-fat meal, with a 21-day washout between treatments. Pharmacokinetic samples were collected through 12 days after dosing. The primary endpoints were the area under the plasma concentration-time curve (AUC) and the maximum concentration of drug in plasma (Cmax). The study employed a prespecified sample size reestimation based on a blind midpoint review of Cmax variability to update the enrollment size to achieve statistical power. Of 118 participants enrolled, 113 received both treatments and underwent pharmacokinetic assessment. The 90% confidence intervals for the geometric least-squares mean ratios for the AUC from 0 h to infinity, the AUC from 0 h to the last quantifiable measurement, and Cmax (test treatment versus reference treatment) were within the bioequivalence range of 0.80 to 1.25 for both drugs, indicating bioequivalence. In this study, a single dose of either treatment was well tolerated overall, with 4% (n = 5) and 3% (n = 3) of participants reporting adverse events considered related to the test and reference treatments, respectively. The dolutegravir-rilpivirine fixed-dose combination tablet is bioequivalent to a combination of separate tablets, and no new safety signals emerged. (This study has been registered at ClinicalTrials.gov under identifier NCT02741557.).

SUBMITTER: Mehta R

PROVIDER: S-EPMC6125541 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Bioequivalence of a Fixed-Dose Combination Tablet of the Complete Two-Drug Regimen of Dolutegravir and Rilpivirine for Treatment of HIV-1 Infection.

Mehta Rashmi R Wolstenholme Allen A Di Lullo Kristin K Fu Caifeng C Joshi Shashidhar S Crauwels Herta H Givens Naomi N Vanveggel Simon S Wynne Brian B Adkison Kimberly K

Antimicrobial agents and chemotherapy 20180827 9

A complete 2-drug regimen of dolutegravir at 50 mg and rilpivirine at 25 mg was approved to treat HIV-1 infection in virologically suppressed patients after demonstrating acceptable efficacy and tolerability. This study investigated the bioequivalence and pharmacokinetics of the fixed-dose combination tablet compared with those of separate tablets. Secondary endpoints were the tolerability and safety of the fixed-dose combination tablet. In this open-label, randomized-sequence, 2-way crossover t ...[more]

PMID: 29987139

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Project description:Availability of a single source review of once-daily fixed-dose single tablet regimen (STR) and multiple tablet fixed-dose regimen (MTR) would optimally inform healthcare providers and policy makers involved in the management of population with human immunodeficiency virus (HIV).We conducted a meta-analysis of published literature to compare patient adherence, clinical, and cost outcomes of STR to MTR.Published literature in English between 2005 and 2014 was searched using Embase, PubMed (Medline in-process), and ClinicalTrials.Gov databases. Two-level screening was undertaken by 2 independent researchers to finalize articles for evidence synthesis. Adherence, efficacy, safety, tolerability, healthcare resource use (HRU), and costs were assessed comparing STR to MTR. A random-effects meta-analysis was performed and heterogeneity examined using meta-regression.Thirty-five articles were identified for qualitative evidence synthesis, of which 9 had quantifiable data for meta-analysis (4 randomized controlled trials and 5 observational studies). Patients on STR were significantly more adherent when compared to patients on MTR of any frequency (odds ratio [OR]: 2.37 [95% CI: 1.68, 3.35], P < 0.001; 4 studies), twice-daily MTR (OR: 2.53 [95% CI: 1.13, 5.66], P = 0.02; 2 studies), and once-daily MTR (OR: 1.81 [95% CI: 1.15, 2.84], P = 0.01; 2 studies). The relative risk (RR) for viral load suppression at 48 weeks was higher (RR: 1.09 [95% CI: 1.04, 1.15], P = .0003; 3 studies) while RR of grade 3 to 4 laboratory abnormalities was lower among patients on STR (RR: 0.68 [95% CI: 0.49, 0.94], P = 0.02; 2 studies). Changes in CD4 count at 48 weeks, any severe adverse events (SAEs), grade 3 to 4 AEs, mortality, and tolerability were found comparable between STR and MTR. Several studies reported significant reduction in HRU and costs among STR group versus MTR.Study depicted comparable tolerability, safety (All-SAE and Grade 3-4 AE), and mortality and fewer Grade 3 to 4 lab abnormalities and better viral load suppression and adherence among patients on FDC-containing STR versus MTR; literature depicted favorable HRU and costs for STRs.These findings may help decision makers especially in resource-poor settings to plan for optimal HIV disease management when the choice of both STRs and MTRs are available.

Project description:BackgroundSuboptimal patient adherence to pharmacological therapy of type 2 diabetes may be due in part to pill burden. One way to reduce pill burden in patients who need multiple medications is to use fixed-dose combinations. Our study aimed to compare the effects of fixed-dose combination versus loose-dose combination therapy on medication adherence and persistence, health care utilization, therapeutic safety, morbidities, and treatment modification in patients with type 2 diabetes over three years.MethodsUsing administrative data, we conducted a retrospective controlled cohort study comparing type 2 diabetes patients who switched from monotherapy to either a fixed-dose combination or a loose-dose combination. Adherence was assessed as the primary endpoint and calculated as the proportion of days covered with medication. After using entropy balancing to eliminate differences in observable baseline characteristics between the two groups, we applied difference-in-difference estimators for each outcome to account for time-invariant unobservable heterogeneity.ResultsOf the 990 type 2 diabetes patients included in our analysis, 756 were taking a fixed-dose combination and 234 were taking a loose-dose combination. We observed a statistically significantly higher change in adherence (year one: 0.22, p<0.001, year two: 0.25, p<0.001, and year three: 0.29, p<0.001) as well as higher persistence and a smaller change in the number of drug prescriptions in each of the three years in the fixed-dose combination group compared to the loose-dose combination group. The differences were most pronounced in patients who were poorly adherent, had a high pill burden, or did not have a severe concomitant disease.ConclusionOur results indicate that taking a fixed-dose combination can lead to a significant improvement in adherence to pharmacological therapy of type 2 diabetes compared to a loose-dose combination. In particular, these findings suggest that reducing pill burden may improve disease management among patients with more complex medication demand and patients who have demonstrated poor medication adherence.

Dataset Information

Bioequivalence of a Fixed-Dose Combination Tablet of the Complete Two-Drug Regimen of Dolutegravir and Rilpivirine for Treatment of HIV-1 Infection.

Publications

Bioequivalence of a Fixed-Dose Combination Tablet of the Complete Two-Drug Regimen of Dolutegravir and Rilpivirine for Treatment of HIV-1 Infection.

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