Aida N Kawuma 1, Stephen I Walimbwa2, Mohammed Lamorde2, Saye Khoo3, Roeland Wasmann1, Paolo Denti 1
1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. 2 Infectious Disease Institute, Makerere University, Kampala, Uganda. 3 The University of Liverpool, Liverpool, UK.
Objectives:
The human immunodeficiency virus (HIV) and malaria often overlap, especially in Sub-Saharan Africa.1 As a result, artemisinin-containing therapies (ACTs) for malaria treatment are regularly co-administered with antiretroviral drugs (ART). Currently, dolutegravir (DTG) based ART regimens are being recommended as first-line therapy across most of Africa.2 The objective of this study was to investigate the population pharmacokinetics (PK) of DTG in co-administration with commonly used ACTs, artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ).
Methods:
Data were available from two PK studies undertaken in healthy Ugandan volunteers, using standard treatment doses of twice-daily AL (80mg + 480 mg ) and once-daily ASAQ (200mg AS + 540mg AQ) with 50 mg DTG once daily given with a moderate fat meal. For each of the studies, rich sampling was performed after repeated DTG dosing on two visits: i) when the volunteers were on DTG alone and ii) on the last day of co-administered antimalarial therapy of either AL or ASAQ. Samples were taken at 0, 1, 2, 3, 4, 8, 12, and 24 hours post-dose. Dolutegravir was quantified using validated reversed-phase liquid chromatography-tandem mass spectrometry with a lower limit of quantification of 0.01 mg/l. Compartmental analysis of the data in NONMEM (v7.4.3) using the first-order conditional estimation method with interaction was employed to develop a model to describe DTG drug disposition and to evaluate the extent to which AL or ASAQ co-administration influenced DTG PK. To account for the effect of body size on clearance and volume parameters, different size descriptors including weight, fat-free mass (FFM) and fat mass were tested.3 We used the final model to simulate trough concentrations (Ctrough) for 1000 virtual patients while on DTG alone (day 7) and after DTG given with either AL or ASAQ (day 10) and tested whether these were maintained above 0.3 mg/l which has been proposed as the DTG protein-adjusted effective concentration (EC90).4
Results:
26 volunteers (61.5% male) were enrolled in both studies. In study one, 14 volunteers received DTG followed by DTG with AL, while in study two 12 volunteers received DTG followed by DTG with ASAQ. The median (range) weight and age for all volunteers was 59.1 kg (41.5 – 76.5) and 28 years (19 – 37), respectively. The PK of DTG following oral administration were adequately described by a two-compartment disposition model with transit compartment absorption. Allometric scaling with fat-free mass was applied to all clearance and volume parameters to account for body size. The typical subject with a FFM of 48.6kg was estimated to have apparent clearance (CL/F) of 0.723 L/h (95% confidence interval (CI): 0.64 – 0.83), central volume (Vc) of 12.8 L (95%CI 11.4 – 14.45), inter-compartmental clearance (Q) of 0.876 L/h (95%CI 0.44 – 1.33) and a peripheral volume (Vp) of 5.39 L (95%CI 3.94 – 8.25). The absorption rate constant (ka) was estimated at 1.63 h-1 (95%CI 1.11 4.71) h-1 with a mean transit time (MTT) of 1.19 h (95%CI 0.98 – 1.59) and 24.5 (95%CI 9.8 – 54.5) transit compartments. Between subject variability (BSV) of 26.2% (95%CI 17 – 33.2) was estimated for CL while between occasion variability (BOV) of 95% (95%CI 63 – 180), 60 % (95%CI 42 – 78) and 18.9 % (95%CI 16 – 35.5) was estimated for ka, MTT and bioavailability (F), respectively. ASAQ co-administration increased DTG clearance by 30% (95%CI 18 – 42) thus lowering overall DTG exposure. However, despite the reduced exposure, simulated trough concentrations for 1000 individuals showed that after co-administration with ASAQ, the Ctrough concentration for 99.6% of the population was above the DTG proposed EC90. We did not detect a significant effect of AL co-administration on the pharmacokinetics of DTG.
Conclusions:
We propose a PK model of DTG in healthy volunteers of African descent, whose CL, Vc and ka are comparable to previous reports.5 However, as opposed to the one-compartment model reported by Zhang et al, we propose a two-compartment model. Although ASAQ co-administration significantly lowers DTG exposure, this interaction is unlikely to be clinically relevant since 99.6% of the patients attain Ctrough concentrations above the target EC90 of DTG. Therefore, standard doses of DTG can be maintained while on standard anti-malaria treatment with AL or ASAQ. However, should ASAQ be used for longer periods, possibly for prophylaxis, this interaction could become clinically relevant.
References:
[1] Tshikuka Mulumba, J. G. et al. Severity of outcomes associated to types of HIV coinfection with TB and malaria in a setting where the three pandemics overlap. J. Community Health 37, 1234–1238 (2012).
[2] WHO | Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV. WHO (2019).
[3] Janmahasatian, S. et al. Quantification of lean bodyweight. Clin. Pharmacokinet. 44, 1051–1065 (2005).
[4] Min, S. et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob. Agents Chemother. 54, 254–8 (2010).
[5] Zhang, J. et al. Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients. Br. J. Clin. Pharmacol. 80, 502–514 (2015).
Reference: PAGE () Abstr 9490 [www.page-meeting.org/?abstract=9490]
Poster: Drug/Disease Modelling - Infection