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Effects of Enzyme Inducers Efavirenz and Tipranavir/Ritonavir on the Pharmacokinetics of the HIV Integrase Inhibitor Dolutegravir

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Effects of Enzyme Inducers Efavirenz and Tipranavir/Ritonavir on the Pharmacokinetics of the HIV Integrase Inhibitor Dolutegravir Eur J Clin Pharmacol (2014) 70:1173–1179 DOI 10.1007/s00228-014-1732-8 CLINICAL TRIAL Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir Ivy Song & Julie Borland & Shuguang Chen & Phyllis Guta & Yu Lou & David Wilfret & Toshihiro Wajima & Paul Savina & Amanda Peppercorn & Stephen Castellino & David Wagner & Louise Hosking & Michael Mosteller & Justin P.Rubio & Stephen C. Piscitelli Received: 7 May 2014 /Accepted: 11 August 2014 /Published online: 23 August 2014 # The Author(s) 2014. This article is published with open access at Springerlink.com Abstract study due to increases in alanine aminotransferase that were Purpose Dolutegravir (DTG) is an unboosted, integrase in- considered related to TPV/r. Co-administration with EFV hibitor for the treatment of HIV infection. Two studies evalu- resulted in decreases of 57, 39 and 75 % in DTG AUC(0–τ), ated the effects of efavirenz (EFV) and tipranavir/ritonavir Cmax and Cτ, respectively. Co-administration with TPV/r re- (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects. sulted in decreases of 59, 46 and 76 % in DTG AUC(0–τ), Cmax Methods The first study was an open-label crossover where and Cτ, respectively. 12 subjects received DTG 50 mg every 24 hours (q24h) for Conclusions Given the reductions in exposure and PK/ 5 days, followed by DTG 50 mg and EFV 600 mg q24h for pharmacodynamic relationships in phase II/III trials, DTG 14 days. The second study was an open-label crossover where should be given at an increased dose of 50 mg twice daily 18 subjects received DTG 50 mg q24h for 5 days followed by when co-administered with EFV or TPV/r, and alternative TPV/r 500/200 mg every 12 hours (q12h) for 7 days and then regimens without inducers should be considered in integrase DTG 50 mg q24h and TPV/r 500/200 mg q12h for a further inhibitor-resistant patients. 5 days. Safety assessments and serial PK samples were col- lected. Non-compartmental PK analysis and geometric mean Keywords Dolutegravir . Drug interaction . Efavirenz . ratios and 90 % confidence intervals were generated. Tipranavir Results The combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r Introduction Electronic supplementary material The online version of this article (doi:10.1007/s00228-014-1732-8) contains supplementary material, Dolutegravir (DTG) is a potent, low-nanomolar inhibitor of which is available to authorized users. HIV integrase. Studies in healthy subjects demonstrate that * : : : : : : I. Song ( ) J.: Borland S. Chen: Y. Lou: D. Wilfret P.: Savina DTG is well tolerated, has low to moderate pharmacokinetic A. Peppercorn S. Castellino D. Wagner M. Mosteller (PK) variability and achieves therapeutic concentrations with S. C. Piscitelli GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, Durham, once-daily dosing [1]. Phase III studies in various patient NC 27709, USA populations demonstrate that DTG has a desirable safety/ e-mail: [email protected] tolerability profile and sustained antiviral activity in combina- tion with other antiretroviral agents in integrase inhibitor P. Guta GlaxoSmithKline, Stockley Park, Uxbridge, UK (INI)-naive- as well as INI-resistant, HIV-infected adults – : [2 5]. L. Hosking J. P. Rubio Dolutegravir is metabolised primarily through UDP- GlaxoSmithKline, Stevenage, UK glucuronosyltransferase (UGT) 1A1 with a minor component ∼ T. Wajima ( 10 %) via CYP3A4 [6]. No clinically significant effects on Shionogi & Co., Ltd., Osaka, Japan DTG exposure requiring a dose adjustment have been 1174 Eur J Clin Pharmacol (2014) 70:1173–1179 observed with UGT1A1 and CYP3A4 inhibitors [7, 8]. How- the mechanism of any potential drug interaction (see Supple- ever, a large decrease in exposure was observed when DTG mentary Material). was co-administered with the CYP3A4 inducer, etravirine [9]. Therefore, it was necessary to evaluate potential interactions Interaction with TPV/r with other antiretroviral agents possessing enzyme-inducing properties. Efavirenz (EFV) is a commonly used drug in HIV- This was a phase I, open-label, single-sequence, three-period, infected individuals. Tipranavir combined with ritonavir steady-state study. Eighteen subjects received DTG (TPV/r) is less commonly used and generally limited to 50 mg q24h for 5 days (period 1). Subjects were then admin- HIV-infected individuals with limited treatment options due istered a lead-inTPV/r 500/200 mg every 12 hours (q12h)for to drug resistance. As both drugs have potential to induce 7 days (period 2) followed by the combination of DTG drug-metabolising enzymes, and because DTG is being stud- 50 mg q24h and TPV/r 500/200 mg q12h for 5 days (period ied across a wide range of HIV-infected populations, drug 3). There was no washout between treatment periods. All interaction studies with both medications were warranted. doses were administered with a moderate-fat meal. Serial PK In vitro, DTG demonstrates minimal or no direct inhibition samples for DTG were collected at the end of the dosing of CYP isozymes, UGT1A1, UGT2B7 and many transporters period of DTG alone (period 1) and DTG + TPV/r (period 3). [P-glycoprotein (P-gp), BCRP, OATP1B1, OATP1B3, MRP2], and is not an inducer of CYP1A2, CYP2B6 or Safety evaluations CYP3A4 [10]. Dolutegravir also had no significant effect on midazolam exposure in healthy subjects [1]. Therefore, the In both studies, safety evaluations [adverse event (AE) primary objective was to evaluate the effect of EFVand TPV/r reporting, clinical chemistry laboratory tests, urinalysis, vital on DTG PK in healthy subjects, not vice versa. signs and electrocardiogram] were performed throughout the study. Given the known hepatotoxicity profile of TPV/r, more frequent monitoring of liver chemistries was performed in the Methods TPV/r study, and conservative stopping criteria were employed such that any subject reaching a grade 2 increase Two studies were conducted in healthy volunteer subjects as in alanine aminotransferase (ALT) or aspartate aminotransfer- judged by physical exam, medical history and laboratory ase (AST) was discontinued from the trial. Both trials were testing. These studies are registered with ClinicalTrials.gov conducted as inpatient studies with subjects housed in the unit (NCT01068925; protocol number ING113096 and for the duration of the study. The studies were conducted in NCT01098526; protocol number ING114005). Adult men accordance with the principles of the Declaration of Helsinki. and women of non-childbearing potential were enrolled. Sub- A written informed consent was obtained from all subjects, jectswereexcludediftheytestedpositiveforHIVorhepatitis and both protocols were approved by the institutional review C antibodies or hepatitis B surface antigen. Subjects were not board of the study sites. allowed to receive any prescription or non-prescription drugs, including vitamins or herbal products, within 7 days of dosing Bioanalytical methods and throughout the study. Subjects had a screening visit (with- in 30 days prior to the first dose of study drug), treatment Dolutegravir and EFV were measured in plasma samples periods and a follow-up visit (7–14 days after the last dose of using validated methods, which consisted of extraction from study drug). plasma by protein precipitation with acetonitrile containing 15 2 2 [ N H7]dolutegravir or [ H4]-efavirenz as the internal stan- Interaction with EFV dards, respectively. The plasma extracts were injected onto a 2.1×50 mm 3.5-micron XBridge™ C18 column (Waters As- This was a phase I, open-label, single-sequence, two-period, sociates, Milford, MA, USA). Dolutegravir was eluted with a steady-state study. Subjects received DTG at a dose of 50 mg mobile phase consisting of 40 % acetonitrile in aqueous 0.1 % (two 25 mg tablets) every 24 hours (q24h) for 5 days (period formic acid, and EFV was eluted with a mobile phase 1), and then the combination of morning DTG 50 mg and consisting of acetonitrile/0.1 % formic acid (65 % v/v)ina evening EFV 600 mg q24h was given for 14 days (period 2). 5-mM ammonium acetate buffer containing 0.1 % acetic acid There was no washout between treatment periods. All doses (35 % v/v). The eluates were detected by using a Sciex API were administered in the fasting state. Serial PK plasma sam- 4000™ (AB Sciex, Framingham, MA, USA) equipped with a ples were collected after each period for DTG, and samples TurboIonSpray® ionisation source with multiple reaction after period 2 were also collected for EFV. The metabolic monitoring (DTG positive ion mode m/z 420>277; internal profile of DTG was evaluated in plasma and urine using standard m/z 428>277; EFV negative ion mode m/z 314> pooled samples for each subject [11] to assist in establishing 243; internal standard m/z 318>247). Data acquisition and Eur J Clin Pharmacol (2014) 70:1173–1179 1175 processing were performed with Analyst 1.4.2 software (AB Ta b l e 1 Genetic polymorphisms evaluated Sciex), and linear regression analysis calculations were per- Gene Polymorphisms formed using the Study Management System, SMS™ 2000 v.2.2 (GlaxoSmithKline, Research Triangle Park, NC, USA). CYP1A2 *1C, *1K ,*7 The calibration range for DTG was 0.020 to 20 μg/mL and for CYP2A6 *2, *4, *5, *6, *7, *9, *11, *17, *20, *21 EFV was 0.10 to 20 μg/mL. Quality control samples prepared CYP2B6 *6, *8, *11, *16, *26, *27, *28 separately at three concentrations were stored with study CYP3A4/3A5 *1B/*3, *6 samples and analysed with each batch of samples against UGT2B7 *2 separately prepared calibration standards. The bias for the analysis of DTG was 4.0 to 8.2 % with precision values of 0.9 to 4.7 % (within-day) and ≤4.5 % (between-day). The bias distribution of polymorphism carrier status between cases and for the analysis of EFV was 1.5 to 12.4 % with precision controls and an assumption of no genetic association, were values of 0.6 to 5.3 % (within-day) and ≤4.4 % (between-day).
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