Allan Kengo (1), Juan Eduardo Resendiz-Galvan (1), Letisha Najjemba (2), Henry Mugerwa (3), Amedeo de Nicolò (4), Antonio D’Avolio (4), Shakir Atoyebi (5), Lubbe Wiesner (1), Elin M. Svensson (6,7), Catriona Waitt (2,5), Paolo Denti (1).
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. (2) Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda. (3) Joint Clinical Research Centre, Research Department, Kampala, Uganda. (4) Laboratory and Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Torino, Torino, Italy. (5) Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom. (6) Department of Pharmacy, Uppsala University, Uppsala, Sweden. (7) Department of Pharmacy, Radboud university medical center, Nijmegen, The Netherlands
Introduction: Boosted protease inhibitors like atazanavir/ritonavir (ATV/r) are commonly prescribed as second-line antiretroviral therapy (ART) for HIV in low-income countries. However, strong drug interactions with rifampicin [1] limit their concomitant use in patients with HIV and tuberculosis [2]. We developed a population pharmacokinetic model to characterize the interaction between ATV/r and rifampicin in plasma and in peripheral blood mononuclear cells (PBMCs).
Methods: Data were available from the DERIVE trial, a single-arm, dose-escalation study conducted among Ugandans living with HIV (no tuberculosis) on ATV/r-based second-line ART for at least 6 months [3]. The trial involved intensive pharmacokinetic sampling at four distinct visits. Initially, participants were on 300/100 mg OD of ATV/r. Visit 2 occurred 14 days after the addition of rifampicin (600 mg OD) and 50 mg BD dolutegravir to their regimen. The dosing frequency of ATV/r was then doubled and Visit 3 was conducted 7 days later. Finally, the dose of rifampicin was also doubled to 1200 mg OD and Visit 4 was done 7 days later. Participant intracellular concentrations were determined from trough samples. Atazanavir (ATV) and ritonavir (RTV) plasma and intracellular concentrations were determined using high performance liquid chromatography with tandem mass spectrometry [3]. Data analysis and simulations were done in NONMEM software.
Results: A total 26 participants (23 female) provided 848 ATV and RTV plasma samples. Additionally, 104 trough intracellular samples were collected for both drugs. The participants’ median (range) age and weight were 44 (23-61) yr and 67 (50-75) kg, respectively. All participants were also on lamivudine and 17 (65%), 8 (31%), 1 (4%) were on tenofovir disoproxil fumarate, zidovudine, and abacavir, respectively.
A two-compartment model with first order transit‑compartment absorption and elimination adequately described the ATV and RTV plasma data. Intracellular trough concentrations were modeled by linking a hypothetical effect compartment to the central compartment, through a partition coefficient (PPC) and an equilibration half-life. The typical clearance (95% CI) of RTV and ATV were 9.7 (8.5–11) L/h and 7.6 (6.3–9.0) L/h, respectively. Rifampicin addition to the regimen was associated with a twofold increase in RTV clearance and a 69% lower bioavailability. Doubling the dosing frequency of RTV partially mitigated this reduction in bioavailability to only 33%.
Adding rifampicin tripled ATV clearance but decreased bioavailability by 53% and absorption rate by 71%. Doubling the dosing frequency restored ATV bioavailability and halved the rifampicin-induced increase in clearance. RTV exposures alone didn’t account for the observed ATV clearance differences, and doubling the rifampicin dose didn’t significantly affect RTV or ATV pharmacokinetics. The PPCs of RTV and ATV between plasma and PBMC were 109% and 54%, respectively, and their equilibration half-lives were estimated to be 1.7 h and 1.1 h, respectively. The simulated median (inter-quartile range) minimum ATV trough concentrations (Ctrough) were 0.688 (0.411–1.12) mg/L without rifampicin, 0.027 (0.015–0.050) mg/L with rifampicin, and 0.697 (0.401–1.17) mg/L with rifampicin and doubled the dosing frequency .
Discussion and conclusion: The observed increase in the clearance of RTV and ATV upon addition of rifampicin to the regimen is mainly attributed to induction of hepatic cytochrome (CYP) 3A4, their principal metabolizing enzyme [1,4]. Interestingly, we observed distinct responses to rifampicin induction on the clearance of RTV and ATV, suggesting differences between their metabolism pathways. This could be because RTV is also metabolized via a less inducible pathway involving CYP2D6 [5].
Furthermore, the induction of CYP3A4 in the gut by rifampicin may have contributed to increased first-pass metabolism of RTV and ATV, reducing their bioavailability [6]. Likewise, the induction of gut p-glycoprotein may explain the observed reduction in absorption speed of ATV because of increased efflux which may prolong drug cycling between enterocytes and the gut lumen [7].
In conclusion, doubling the dosing frequency of ATV and RTV reduced the effects of rifampicin induction on their clearance and sufficiently restored their exposure when co-administered in patients with HIV.
References:
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[6] Glaeser H, Drescher S, Eichelbaum M, Fromm MF. Influence of rifampicin on the expression and function of human intestinal cytochrome P450 enzymes. Br J Clin Pharmacol. 2005 Feb;59(2):199–206.
[7] Sodhi JK, Benet LZ. The Necessity of Using Changes in Absorption Time to Implicate Intestinal Transporter Involvement in Oral Drug-Drug Interactions. AAPS Journal. 2020 Sep 1;22(5).
Reference: PAGE 32 (2024) Abstr 11045 [www.page-meeting.org/?abstract=11045]
Poster: Drug/Disease Modelling - Infection