{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["72(6)"],"submitter":["Song I"],"pubmed_abstract":["Dolutegravir (DTG) is primarily metabolized by UGT1A1 with CYP3A as a minor route. Carbamazepine (CBZ) is a potent inducer of these enzymes; thus, the effect of oral extended-release CBZ on DTG pharmacokinetics (PK) was evaluated to provide dose recommendation when co-administered.This was a single-center, open-label, fixed-sequence, crossover study in healthy adults. Subjects received three treatments: DTG 50 mg every 24 h (q24h) × 5 days in period 1, followed by CBZ 100 mg every 12 h (q12h) × 3 days, then 200 mg q12h × 3 days, then 300 mg q12h × 10 days in period 2, and DTG 50 mg q24h + CBZ 300 mg q12h × 5 days in period 3. No washout intervals occurred. Each dose was administered with a moderate-fat meal. Serial PK samples for DTG were collected on day 5 of periods 1 and 3. Plasma DTG PK parameters were determined with non-compartmental analysis. Geometric least-squares mean ratios (GMRs) and 90 % confidence intervals (CIs) were generated by the mixed-effect model for within-subject treatment comparisons. Safety assessments were performed throughout the study.Sixteen subjects enrolled; 14 completed the study. CBZ significantly reduced DTG exposure: GMRs (90 % CI) for DTG + CBZ versus DTG alone were 0.51 (0.48-0.549), 0.67 (0.61-0.73), and 0.27 (0.24-0.31) for area under the curve from time zero to the end of the dosing interval (AUC(0-?)), maximum observed plasma concentration (Cmax), and plasma concentration at the end of the dosing interval (C?), respectively. DTG alone and co-administered with CBZ was well tolerated.Integrase strand transfer inhibitor-naive subjects taking CBZ should receive DTG 50 mg twice daily versus once daily, as is recommended with other potent UGT1A/CYP3A inducers. ClinicalTrials.gov: NCT01967771."],"journal":["European journal of clinical pharmacology"],"pagination":["665-70"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4865535"],"repository":["biostudies-literature"],"pubmed_title":["Effect of carbamazepine on dolutegravir pharmacokinetics and dosing recommendation."],"pmcid":["PMC4865535"],"pubmed_authors":["Choukour M","Weller S","Borland J","Piscitelli S","Jerva F","Patel J","Song I","Wynne B"],"additional_accession":[]},"is_claimable":false,"name":"Effect of carbamazepine on dolutegravir pharmacokinetics and dosing recommendation.","description":"Dolutegravir (DTG) is primarily metabolized by UGT1A1 with CYP3A as a minor route. Carbamazepine (CBZ) is a potent inducer of these enzymes; thus, the effect of oral extended-release CBZ on DTG pharmacokinetics (PK) was evaluated to provide dose recommendation when co-administered.This was a single-center, open-label, fixed-sequence, crossover study in healthy adults. Subjects received three treatments: DTG 50 mg every 24 h (q24h) × 5 days in period 1, followed by CBZ 100 mg every 12 h (q12h) × 3 days, then 200 mg q12h × 3 days, then 300 mg q12h × 10 days in period 2, and DTG 50 mg q24h + CBZ 300 mg q12h × 5 days in period 3. No washout intervals occurred. Each dose was administered with a moderate-fat meal. Serial PK samples for DTG were collected on day 5 of periods 1 and 3. Plasma DTG PK parameters were determined with non-compartmental analysis. Geometric least-squares mean ratios (GMRs) and 90 % confidence intervals (CIs) were generated by the mixed-effect model for within-subject treatment comparisons. Safety assessments were performed throughout the study.Sixteen subjects enrolled; 14 completed the study. CBZ significantly reduced DTG exposure: GMRs (90 % CI) for DTG + CBZ versus DTG alone were 0.51 (0.48-0.549), 0.67 (0.61-0.73), and 0.27 (0.24-0.31) for area under the curve from time zero to the end of the dosing interval (AUC(0-?)), maximum observed plasma concentration (Cmax), and plasma concentration at the end of the dosing interval (C?), respectively. DTG alone and co-administered with CBZ was well tolerated.Integrase strand transfer inhibitor-naive subjects taking CBZ should receive DTG 50 mg twice daily versus once daily, as is recommended with other potent UGT1A/CYP3A inducers. ClinicalTrials.gov: NCT01967771.","dates":{"release":"2016-01-01T00:00:00Z","publication":"2016 Jun","modification":"2021-02-20T02:14:07Z","creation":"2019-03-27T02:13:34Z"},"accession":"S-EPMC4865535","cross_references":{"pubmed":["26898568"],"doi":["10.1007/s00228-016-2020-6"]}}