CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

428 EFFECT OF SORBITOL ON 3TC PK AFTER ADMINISTRATION OF LAMIVUDINE SOLUTION IN ADULTS Kimberly K. Adkison 1 , Cynthia McCoig 2 , Allen Wolstenholme 3 , Yu Lou 4 , Zhiping Zhang 4 , Amy Eld 3 , Katy Hayward 5 , Mark Shaefer 1

1 ViiV Hlthcare, Rsr Triangle Park, NC, USA, 2 ViiV Hlthcare, Tres Cantos, Madrid, Spain, 3 GlaxoSmithKline, Collville, PA, USA, 4 PAREXEL Intl, Durham, NC, USA, 5 ViiV Hlthcare, Brentford, UK Background: Several relative bioavailability studies of lamivudine (3TC) in HIV-infected children (0.5-12y) showed that EPIVIR® oral solution yielded 30-57% lower plasma 3TC exposures than various tablet formulations. It was hypothesized that the lower 3TC concentrations observed in these pediatric studies could be due to an interaction between 3TC and sorbitol, an excipient in co-administered liquid medications. This study was conducted to evaluate the effect of sorbitol on the single dose pharmacokinetics (PK) of 3TC oral solution. Methods: Study 204857 (NCT02634073) was an open label, randomized, 4-way William’s crossover study in healthy adult subjects. Subjects were randomized to receive each treatment in 1 of 4 sequences with a ≥7 day between-treatment washout period. Treatments included a single dose of 3TC 300 mg (Treatment A; reference), 3TC 300 mg + sorbitol 3.2 g (Treatment B), 3TC 300 mg + sorbitol 10.2 g (Treatment C), and 3TC 300 mg + sorbitol 13.4 g (Treatment D). 3TC was administered as EPIVIR 10mg/mL oral solution following an 8-hour fast. Serial PK samples were collected after each treatment. Test/reference geometric least squares (GLS) means ratio and associated 90% confidence intervals (CI) of non-compartmental PK parameters (log-transformed) were determined by analysis of variance using a mixed effects model. Safety assessments were performed throughout the study. Results: Of 37 subjects screened, 16 were randomized and completed the study. Selected 3TC PK parameters and statistical comparisons to reference are summarized in the Table. Sorbitol had a dose-dependent effect on 3TC PK with 28%, 52%, and 55% lower Cmax, 20%, 39%, and 44% lower AUC(0-24), and 14%, 32%, and 36% lower AUC(0-∞) when co-administered with 3.2 g, 10.2 g, and 13.4 g sorbitol, respectively. The median 3TC Tmax occurred between 0.75 to 1.26 h post dose, with later Tmax associated with sorbitol co- administration. 3TC with and without sorbitol containing solutions were well tolerated. There were no deaths or SAEs. A total of 3 subjects reported 5 AEs; 1 was drug-related. Conclusion: Co-administration of single doses of 3TC and sorbitol solutions under fasted conditions resulted in decreased 3TC plasma exposures. Sorbitol had the greatest impact on 3TC Cmax and AUC(0-24), suggesting that an absorption-based interaction is the likely mechanism for the reduction in 3TC exposures observed in this study.

Poster and Themed Discussion Abstracts

429 CRUSHING OF DOLUTEGRAVIR COMBINATION TABLETS INCREASES DOLUTEGRAVIR EXPOSURE Marieke Roskam-Kwint 1 , Pauline Bollen 1 , Angela Colbers 1 , Marjolijn Duisenberg-van Essenberg 2 , Veroniek Harbers 1 , Reinout van Crevel 1 , David M. Burger 1 1 Radboud Univ Med Cntr, Nijmegen, Netherlands, 2 Elisabeth–TweeSteden Ziekenhuis, Tilburg, Netherlands

Background: If HIV-patients are unconscious or cannot swallow tablets for other reasons, antiretroviral medication is often crushed and dissolved prior to administration. Crushing can influence pharmacokinetics (PK) leading to altered drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Currently, there is no information about crushing the branded fixed-dose combination of dolutegravir/abacavir/lamivudine (TRI), therefore crushing TRI is not recommended. In addition, a PK interaction between dolutegravir (DTG) and enteral nutrition is possible, based on the known interaction between DTG and cations in antacids and supplements. Methods: An open-label, 3-period, randomized, cross-over, trial in 22 healthy volunteers was conducted. Subjects randomly received a single dose of TRI with a 7-day washout period. Reference treatment A: TRI whole tablet fasting, intervention treatments B: crushed and suspended TRI fasting and C: crushed and suspended TRI, followed by drinking drip feed (250kcal) within 5 minutes after TRI intake. To show bioequivalence between reference A and B and C a 48-h PK profile was measured for DTG. Geometric mean ratios (GMR) with 90% confidence interval (CI) for AUC0-inf and Cmax were calculated. Bioequivalence was accepted when the 90% CI was within 80-125% for AUC and Cmax. Safety and tolerability were evaluated. Results: 22 healthy volunteers (21 Caucasian and 1 mixed-race, 10 female), 25 (18-54) years and BMI 23 (20-27) kg/m2 (median (range)) completed the trial. For crushed TRI vs whole tablet, the GMR (90% CI) of DTG Cmax was 129% (123-136), of DTG AUC0-inf 126% (119-132) and DTG half-life 101% (97-104). For crushed TRI with enteral nutrition vs whole tablet, the GMR (90% CI) of DTG Cmax was 122% (115-128), of DTG AUC0-inf 118% (112-125) and DTG half-life 98% (95-102). No SAEs were reported during the trial. Conclusion: AUC0-inf and Cmax fell outside the predefined bioequivalence range. DTG exposure was 26% higher after crushing and 18% higher after crushing and intake with enteral nutrition. The maximum concentrations showed the same trend. The half-life was similar in all treatments, therefore increased DTG exposure is probably caused by enhanced absorption. Enteral nutrition did not negatively affect DTG absorption. Although no dose-limiting toxicity of DTG is observed to date, caution is warranted if chronic administration of crushed TRI is needed.

CROI 2017 179