A Study to Evaluate Doravirine Pharmacokinetics When Coadministered With Acid‐Reducing Agents

Abstract

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus type 1 infection. Because of potential concomitant administration with acid-reducing agents, a drug-interaction trial was conducted to evaluate the potential impact of these types of medications on doravirine pharmacokinetics. In an open-label, 3-period, fixed-sequence trial, healthy adult participants received the following:period 1,a single dose of doravirine 100 mg;period 2,coadministration of a single dose of doravirine 100 mg and an antacid (1600 mg aluminum hydroxide, 1600 mg magnesium hydroxide, and 160 mg simethicone); period 3, 40 mg pantoprazole once daily on days 1-5 coadministered with a single dose of doravirine 100 mg on day 5. There was a minimum 10-day washout between periods. Plasma samples for pharmacokinetic evaluation were collected, and safety was assessed. Fourteen participants (8 male, 6 female) were enrolled, and 13 completed the trial. Geometric mean ratios (90% confidence intervals) for doravirine AUC 0-inf ,C max ,and C 24 for doravirine + antacid/doravirine were 1.01 (0.92-1.11), 0.86 (0.74-1.01), and 1.03 (0.94-1.12), respectively, and for doravirine + pantoprazole/doravirine were 0.83 (0.76-0.91), 0.88 (0.76-1.01), and 0.84 (0.77-0.92), respectively. Doravirine was generally well tolerated administered alone or with either of the acid-reducing agents. Coadministration of an aluminum/magnesium-containing antacid or pantoprazole did not have a clinically meaningful effect on doravirine pharmacokinetics, supporting the use of acid-reducing agents with doravirine.

Clinical Pharmacokinetics of the Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Doravirine: An Assessment of the Effect of Patient Characteristics and Drug–Drug Interactions

“…Steady-state AUC was selected as the exposure measure from which to judge clinical relevance from a safety perspective, as this parameter is an integration of concentrations over the 24-h dosing interval in which individuals are exposed to doravirine at steady state. In phase I trials, there was no evidence that the incidence of overall AEs or specific AEs was temporally associated with doravirine T max [11,15,[20][21][22][23][24][25][26][27][28][29][30][31], therefore suggesting that C max does not play a major role in safety or tolerability. In the phase IIb trial, there was no evidence of exposure-or dose-related toxicities across the range of 25-200 mg doses evaluated, and no meaningful association between doravirine steady-state exposure and the incidence of neuropsychiatric AEs or fasting lipid levels that would further limit the exposure of doravirine from a safety perspective [17].…”

“…Co-administration of either an aluminum-/magnesium-containing antacid or the proton-pump inhibitor pantoprazole with doravirine did not have a clinically meaningful effect on doravirine pharmacokinetics ( Table 2, Fig. 3) [28]. Slight decreases (12-17%) in doravirine AUC 0-∞ , C max , and C 24 following co-administration with pantoprazole, and in doravirine C max following co-administration with an antacid, were not considered clinically meaningful on the basis of the established clinical bounds for doravirine.…”

“…Slight decreases (12-17%) in doravirine AUC 0-∞ , C max , and C 24 following co-administration with pantoprazole, and in doravirine C max following co-administration with an antacid, were not considered clinically meaningful on the basis of the established clinical bounds for doravirine. Gastric acid-reducing agents may be co-administered with doravirine without need for dose adjustments or restrictions [28].…”

“…Doravirine was shown to have limited potential for clinically meaningful DDIs based on data obtained from in vitro studies of drug-metabolizing enzymes and drug transporters [10,45] and clinical studies [15,20,21,[26][27][28][29][30][31]. Since doravirine is a substrate of CYP3A4 [10], the most likely route of its involvement in DDIs is via inhibition and induction of CYP3A activity by strong and moderate CYP3A inhibitors/inducers.…”

Pharmacokinetics, safety and tolerability of long‐acting parenteral intramuscular injection formulations of doravirine

“…At the therapeutic dose of 100 mg, orally administered doravirine is rapidly absorbed; the time to maximum concentration (T max ) and half‐life (t 1/2 ) are ~2 hours and ~15 hours, respectively, supporting once‐daily administration 7 . Doravirine may be administered without regard to food and possesses a favourable drug interaction profile, with no expected clinically relevant effects on the disposition of commonly co‐administered drugs 9‐17 . Being primarily eliminated via cytochrome P450 (CYP)3A4‐mediated hepatic metabolism, 18 meaningful reductions in doravirine exposure occur with moderate and strong CYP3A4 inducers 11 ; however, there is low interaction potential for other major drug‐metabolizing agents or transporters 14 …”