The Effect of Rifampicin on Darunavir, Ritonavir, and Dolutegravir Exposure within Peripheral Blood Mononuclear Cells: a Dose Escalation Study

Amedeo De Nicolò, Andrea Calcagno, Ilaria Motta, Elisa De Vivo, Antonio D'Avolio, Giovanni Di Perri, Lubbe Wiesner, Isma-Eel Ebrahim, Gary Maartens, Catherine Orrell, Helen McIlleron, Amedeo De Nicolò, Andrea Calcagno, Ilaria Motta, Elisa De Vivo, Antonio D'Avolio, Giovanni Di Perri, Lubbe Wiesner, Isma-Eel Ebrahim, Gary Maartens, Catherine Orrell, Helen McIlleron

Abstract

Ritonavir-boosted darunavir (DRV/r) and dolutegravir (DTG) are affected by induction of metabolizing enzymes and efflux transporters caused by rifampicin (RIF). This complicates the treatment of people living with HIV (PLWH) diagnosed with tuberculosis. Recent data showed that doubling DRV/r dose did not compensate for this effect, and hepatic safety was unsatisfactory. We aimed to evaluate the pharmacokinetics of DRV, ritonavir (RTV), and DTG in the presence and absence of RIF in peripheral blood mononuclear cells (PBMCs). PLWH were enrolled in a dose-escalation crossover study with 6 treatment periods of 7 days. Participants started with DRV/r 800/100 mg once daily (QD), RIF and DTG were added before the RTV dose was doubled, and then they received DRV/r 800/100 twice daily (BD) and then 1,600/200 QD or vice versa. Finally, RIF was withdrawn. Plasma and intra-PBMC drug concentrations were measured through validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Seventeen participants were enrolled but only 4 completed all study phases due to high incidence of liver toxicity. Intra-PBMC DRV trough serum concentration (Ctrough) after the addition of RIF dropped from a median (interquartile range [IQR]) starting value of 261 ng/mL (158 to 577) to 112 ng/mL (18 to 820) and 31 ng/mL (12 to 331) for 800/100 BD and 1,600/200 QD DRV/r doses, respectively. The DRV intra-PBMC/plasma ratio increased significantly (P = 0.003). DTG and RIF intra-PBMC concentrations were in accordance with previous reports in the absence of RIF or DRV/r. This study showed a differential impact of enzyme and/or transporter induction on DRV/r concentrations in plasma and PBMCs, highlighting the usefulness of studying intra-PBMC pharmacokinetics with drug-drug interactions. (This study has been registered at ClinicalTrials.gov under registration no. NCT03892161.).

Keywords: PBMC; darunavir; dolutegravir; drug interactions; drug-drug interaction; pharmacokinetics; rifampicin.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIG 1
FIG 1
Distribution of the intra-PBMC DRV trough concentrations (left) and intra-PBMC/plasma concentration ratios (right) in each treatment period. Whiskers represents the first and fourth quartile, respectively; circles represent mild outliers (>2 standard deviations), and asterisks represent extreme outliers (>3 standard deviations).
FIG 2
FIG 2
Distribution of the intra-PBMC RTV trough concentrations (left) and intra-PBMC/plasma trough concentration ratios (right) in each treatment period. Whiskers represents the first and fourth quartile, respectively; circles represent mild outliers (>2 standard deviations), and asterisks represent extreme outliers (>3 standard deviations).
FIG 3
FIG 3
Distribution of the intra-PBMC DTG trough concentrations (left) and intra-PBMC/plasma trough concentration ratios (right) in each treatment period. Whiskers represents the first and fourth quartile, respectively; circles represent mild outliers (>2 standard deviations), and asterisks represent extreme outliers (>3 standard deviations).
FIG 4
FIG 4
Distribution of the plasma and intra-PBMC RIF peak concentrations (left) and intra-PBMC/plasma peak concentration ratios (right) in each treatment period. Whiskers represents the first and fourth quartile, respectively; circles represent mild outliers (>2 standard deviations), and asterisks represent extreme outliers (>3 standard deviations).

References

    1. Lefebvre E, Schiffer CA. 2008. Resilience to resistance of HIV-1 protease inhibitors: profile of darunavir. AIDS Rev 10:131–142.
    1. Brown KC, Paul S, Kashuba AD. 2009. Drug interactions with new and investigational antiretrovirals. Clin Pharmacokinet 48:211–241. 10.2165/00003088-200948040-00001.
    1. Drewe J, Gutmann H, Fricker G, Torok M, Beglinger C, Huwyler J. 1999. HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharmacol 57:1147–1152. 10.1016/S0006-2952(99)00026-X.
    1. Perloff MD, Von Moltke LL, Marchand JE, Greenblatt DJ. 2001. Ritonavir induces P-glycoprotein expression, multidrug resistance-associated protein (MRP1) expression, and drug transporter-mediated activity in a human intestinal cell line. J Pharm Sci 90:1829–1837. 10.1002/jps.1133.
    1. Rehman S, Nabi B, Fazil M, Khan S, Bari NK, Singh R, Ahmad S, Kumar V, Baboota S, Ali J. 2017. Role of P-glycoprotein inhibitors in the bioavailability enhancement of solid dispersion of darunavir. Biomed Res Int 2017:8274927. 10.1155/2017/8274927.
    1. Rittweger M, Arasteh K. 2007. Clinical pharmacokinetics of darunavir. Clin Pharmacokinet 46:739–756. 10.2165/00003088-200746090-00002.
    1. Lutz JD, Kirby BJ, Wang L, Song Q, Ling J, Massetto B, Worth A, Kearney BP, Mathias A. 2018. Cytochrome P450 3A induction predicts P-glycoprotein induction; part 1: establishing induction relationships using ascending dose rifampin. Clin Pharmacol Ther 104:1182–1190. 10.1002/cpt.1073.
    1. Lutz JD, Kirby BJ, Wang L, Song Q, Ling J, Massetto B, Worth A, Kearney BP, Mathias A. 2018. Cytochrome P450 3A induction predicts P-glycoprotein induction; part 2: prediction of decreased substrate exposure after rifabutin or carbamazepine. Clin Pharmacol Ther 104:1191–1198. 10.1002/cpt.1072.
    1. Roberts O, Khoo S, Owen A, Siccardi M. 2017. Interaction of rifampin and darunavir-ritonavir or darunavir-cobicistat in vitro. Antimicrob Agents Chemother 61:e01776-16. 10.1128/AAC.01776-16.
    1. Ebrahim I, Maartens G, Wiesner L, Orrell C, Smythe W, McIlleron H. 2020. Pharmacokinetic profile and safety of adjusted doses of darunavir/ritonavir with rifampicin in people living with HIV. J Antimicrob Chemother 75:1019–1025. 10.1093/jac/dkz522.
    1. Dyavar SR, Gautam N, Podany AT, Winchester LC, Weinhold JA, Mykris TM, Campbell KM, Alnouti Y, Fletcher CV. 2019. Assessing the lymphoid tissue bioavailability of antiretrovirals in human primary lymphoid endothelial cells and in mice. J Antimicrob Chemother 74:2974–2978. 10.1093/jac/dkz273.
    1. Fletcher CV, Staskus K, Wietgrefe SW, Rothenberger M, Reilly C, Chipman JG, Beilman GJ, Khoruts A, Thorkelson A, Schmidt TE, Anderson J, Perkey K, Stevenson M, Perelson AS, Douek DC, Haase AT, Schacker TW. 2014. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc Natl Acad Sci USA 111:2307–2312. 10.1073/pnas.1318249111.
    1. Mitchell C, Roemer E, Nkwopara E, Robbins B, Cory T, Rue T, Fletcher CV, Frenkel L. 2014. Correlation between plasma, intracellular, and cervical tissue levels of raltegravir at steady-state dosing in healthy women. Antimicrob Agents Chemother 58:3360–3365. 10.1128/AAC.02757-13.
    1. D'Avolio A, Simiele M, Calcagno A, Siccardi M, Larovere G, Agati S, Baietto L, Cusato J, Tettoni M, Sciandra M, Trentini L, Di Perri G, Bonora S. 2013. Intracellular accumulation of ritonavir combined with different protease inhibitors and correlations between concentrations in plasma and peripheral blood mononuclear cells. J Antimicrob Chemother 68:907–910. 10.1093/jac/dks484.
    1. De Nicolò A, Simiele M, Calcagno A, Abdi AM, Bonora S, Di Perri G, D'Avolio A. 2014. Intracellular antiviral activity of low-dose ritonavir in boosted protease inhibitor regimens. Antimicrob Agents Chemother 58:4042–4047. 10.1128/AAC.00104-14.
    1. Arab-Alameddine M, Lubomirov R, Fayet-Mello A, Aouri M, Rotger M, Buclin T, Widmer N, Gatri M, Ledergerber B, Rentsch K, Cavassini M, Panchaud A, Guidi M, Telenti A, Decosterd LA, Csajka C, Swiss HIV Cohort Study. 2014. Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals. J Antimicrob Chemother 69:2489–2498. 10.1093/jac/dku131.
    1. Konig SK, Herzog M, Theile D, Zembruski N, Haefeli WE, Weiss J. 2010. Impact of drug transporters on cellular resistance towards saquinavir and darunavir. J Antimicrob Chemother 65:2319–2328. 10.1093/jac/dkq324.
    1. Tibotec, Inc. 2008. Prezista. Tibotec, Inc., Yardley, PA. .
    1. Shehu AI, Lu J, Wang P, Zhu J, Wang Y, Yang D, McMahon D, Xie W, Gonzalez FJ, Ma X. 2019. Pregnane X receptor activation potentiates ritonavir hepatotoxicity. J Clin Invest 129:2898–2903. 10.1172/JCI128274.
    1. Sulkowski MS. 2003. Hepatotoxicity associated with antiretroviral therapy containing HIV-1 protease inhibitors. Semin Liver Dis 23:183–194. 10.1055/s-2003-39949.
    1. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. 2000. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 283:74–80. 10.1001/jama.283.1.74.
    1. Decloedt EH, McIlleron H, Smith P, Merry C, Orrell C, Maartens G. 2011. Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin with adjusted doses of lopinavir-ritonavir tablets. Antimicrob Agents Chemother 55:3195–3200. 10.1128/AAC.01598-10.
    1. McIlleron H, Hundt H, Smythe W, Bekker A, Winckler J, van der Laan L, Smith P, Zar HJ, Hesseling AC, Maartens G, Wiesner L, van Rie A. 2016. Bioavailability of two licensed paediatric rifampicin suspensions: implications for quality control programmes. Int J Tuber Lung Dis 20:915–919. 10.5588/ijtld.15.0833.
    1. Baietto L, Calcagno A, Motta I, Baruffi K, Poretti V, Di Perri G, Bonora S, D'Avolio A. 2015. A UPLC-MS-MS method for the simultaneous quantification of first-line antituberculars in plasma and in PBMCs. J Antimicrob Chemother 70:2572–2575. 10.1093/jac/dkv148.
    1. Asaumi R, Toshimoto K, Tobe Y, Hashizume K, Nunoya KI, Imawaka H, Lee W, Sugiyama Y. 2018. Comprehensive PBPK model of rifampicin for quantitative prediction of complex drug-drug interactions: CYP3A/2C9 induction and OATP inhibition effects. CPT Pharmacometrics Syst Pharmacol 7:186–196. 10.1002/psp4.12275.
    1. Rockwood N, Meintjes G, Chirehwa M, Wiesner L, McIlleron H, Wilkinson RJ, Denti P. 2016. HIV-1 coinfection does not reduce exposure to rifampin, isoniazid, and pyrazinamide in South African tuberculosis outpatients. Antimicrob Agents Chemother 60:6050–6059. 10.1128/AAC.00480-16.
    1. Shitara Y, Takeuchi K, Horie T. 2013. Long-lasting inhibitory effects of saquinavir and ritonavir on OATP1B1-mediated uptake. J Pharm Sci 102:3427–3435. 10.1002/jps.23477.
    1. Cory TJ, Winchester LC, Robbins BL, Fletcher CV. 2015. A rapid spin through oil results in higher cell-associated concentrations of antiretrovirals compared with conventional cell washing. Bioanalysis 7:1447–1455. 10.4155/bio.15.70.
    1. Ford J, Boffito M, Wildfire A, Hill A, Back D, Khoo S, Nelson M, Moyle G, Gazzard B, Pozniak A. 2004. Intracellular and plasma pharmacokinetics of saquinavir-ritonavir, administered at 1,600/100 milligrams once daily in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 48:2388–2393. 10.1128/AAC.48.7.2388-2393.2004.
    1. Khoo SH, Hoggard PG, Williams I, Meaden ER, Newton P, Wilkins EG, Smith A, Tjia JF, Lloyd J, Jones K, Beeching N, Carey P, Peters B, Back DJ. 2002. Intracellular accumulation of human immunodeficiency virus protease inhibitors. Antimicrob Agents Chemother 46:3228–3235. 10.1128/AAC.46.10.3228-3235.2002.
    1. Rabie H, Rawizza H, Zuidewind P, Winckler J, Zar H, Van Rie A, Wiesner L, McIlleron H. 2019. Pharmacokinetics of adjusted-dose 8-hourly lopinavir/ritonavir in HIV-infected children co-treated with rifampicin. J Antimicrob Chemother 74:2347–2351. 10.1093/jac/dkz171.
    1. De Nicolò A, Ianniello A, Ferrara M, Avataneo V, Cusato J, Antonucci M, De Vivo E, Waitt C, Calcagno A, Trentalange A, Muccioli G, Bonora S, Di Perri G, D'Avolio A. 2021. Validation of a UHPLC-MS/MS method to quantify twelve antiretroviral drugs within peripheral blood mononuclear cells from people living with HIV. Pharmaceuticals (Basel) 14:12. 10.3390/ph14010012.
    1. Simiele M, D'Avolio A, Baietto L, Siccardi M, Sciandra M, Agati S, Cusato J, Bonora S, Di Perri G. 2011. Evaluation of the mean corpuscular volume of peripheral blood mononuclear cells of HIV patients by a coulter counter to determine intracellular drug concentrations. Antimicrob Agents Chemother 55:2976–2978. 10.1128/AAC.01236-10.

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