Suthunya Chupradit1, Dalton C. Wamalwa3, Elizabeth Maleche-Obimbo3, Adeodata R. Kekitiinwa4, Juliet Mwanga-Amumpaire5, Elizabeth A. Bukusi6, Winstone M. Nyandiko7, Joseph K. Mbuthia8, Alistair Swanson9 and DNDi Clinical Team9, Tim R. Cressey10,11, Baralee Punyawudho1, Victor Musiime2
1Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand; 2Joint Clinical Research Centre, Kampala, Uganda; 3Department of Paediatrics and Child Health, University of Nairobi, Nairobi, Kenya; 4Baylor College of Medicine Children’s Foundation, Kampala, Uganda; 5Epicentre, Mbarara, Uganda; 6Centre for Microbiology Research, Kenya Medical Research Institute, Kisumu, Kenya; 7Department of Child Health and Paediatrics - Moi University, AMPATH and Moi Teaching and Referral Hospital, Eldoret, Kenya; 8Gertrude’s Children’s Hospital, Nairobi, Kenya; 9Drugs for Neglected Diseases Initiative (Switzerland, Kenya and USA); 10AMS/IRD-MIVEGEC, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; 11Department of Molecular & Clinical Pharmacology, University of Liverpool, UK.
Background: Lopinavir/ritonavir (LPV/r) is widely used for the treatment of children living with HIV (CLWH) younger than 3 years of age as part of combination antiretroviral therapy (ART) (1). Due to the poor palatability and cold storage requirements of the original liquid formulation of LPV/r, novel solid formations of LPV/r have been sought. The first solid formulation for young children approved by US Food and Drug Administration was LPV/r oral pellets (or mini – ‘melt’ tablets), which contained 40 mg lopinavir/10 mg ritonavir (40/10 mg) per capsule (Cipla Ltd, India). For administration, the capsules are opened, and the LPV/r pellets are mixed with milk or food. Also, this solid formulation does not need refrigerated storage like the LPV/r liquid (2). The LIVING study assessed the effectiveness, safety, efficacy, acceptability, and pharmacokinetics (PK) of the LPV/r pellets in routine care in Africa. Here, we describe the PK of LPV/r in African children receiving LPV/r pellets twice daily (BID) according to the World Health Organization (WHO) weight bands dosing.
Method: Children enrolled in the LIVING study in Kenya and Uganda [ClinicalTrials.gov Identifier: NCT02346487] who received LPV/r pellets BID and ABC/3TC (60/30 mg) dispersible tablets were included. LPV/r oral pellets were administered according to WHO weight bands: 2, 3, 4, 5, and 6 LPV/r capsules, twice daily, for children 3–5.9 kg, 6–9.9 kg, 10–13.9 kg, 14–19.9 kg, and 20–24.9 kg, respectively. During study follow-up, blood samples were collected for sparse PK evaluation at 1 month, and then every 6 months afterwards. Population PK models of LPV and RTV were developed separately using a nonlinear mixed-effects modeling approach (NONMEM®). Once the final models of LPV and RTV were obtained, the influence of RTV concentrations on LPV CL/F was investigated using linear, exponential, and maximum effect (Emax) models (3). Model evaluation was performed using Goodness-of-fit plots and visual predictive checks. Bodyweight was included as a covariate a priori. Gender and malnutrition status [identified by weight-for-age z-score (WAZ), classified as normal (WZA > -2), moderate (-3 < WAZ < -2), and severe (WAZ < -3)] were investigated as covariates using a stepwise approach. Using the final model, simulations were performed using a standardized in silico paediatric population with demographics representative of CLWH in Africa to predict LPV exposure across WBs. The LPV target exposure was an area under the curve (AUC0-12) of 40-160 mg.h/mL reported in older children (4).
Results: A total of 2,998 LPV/r plasma concentrations were available from 514 children (52% female). The mean (SD) age was 3.28 ± 2.01 (range, 0.3-12.4) years, body weight was 12.56 ± 3.97 (4.6-25) kg, and 17% and 9% of children were classified as moderately and severely underweight, respectively. The pharmacokinetics of LPV and RTV were best described by one-compartment models with first-order absorption (with lag-time) and elimination. Bodyweight influenced LPV and RTV clearance (CL/F) and apparent volume of distribution (V/F) using allometric scaling, but the inclusion of maturational changes as a function of age did not improve the model fit. Malnutrition status did not influence the PK of LPV and RTV. Population estimates of LPV CL/F (IIV), V/F (IIV), Ka (IIV), lag time were 5.70 L/h/13.6 kg (14.6%), 29.90 L/13.6 kg (31.90%), 0.50 h-1 (88.40%) and 0.46 h, respectively. Population estimates of RTV CL/F (IIV), V/F (IIV), Ka and lag time of RTV were 11.40 L/h/13.6 kg (32.60%), 38.8 L/13.6 kg (74.10), 0.16 h-1 and 0.29 h, respectively. The dynamic influence of RTV concentrations on LPV CL/F was modeled using an Emax model as direct inhibition. Emax was fixed to 0.9, while RTV concentration producing half of the maximal inhibition effect (IC50) was estimated to be 0.049 mg/L. Simulations predicted target LPV exposures were achieved in African children with this solid formulation across the WHO weight bands.
Conclusion: LPV drug exposures in African children weighing 3.0 to 24.9 kg using the generic LPV/r pellets dosed per WHO weight bands were comparable to those reported with the original liquid and tablet formulations.
References:
(1) World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendation for a public health approach. 2nd. World Health Organization; Geneva, Switzerland: 2016.
(2) Fact Sheet on Lopinavir And Ritonavir (LPV/R) Oral Pellets. Interagency Task Team. September 2015.
(3) Dayneka NL, Garg V, Jusko WJ. Comparison of four basic models of indirect pharmacodynamic responses. J Pharmacokinet Biopharm. 1993;21:457–78.
(4) Pinto JA, Capparelli EV, Warshaw M, et al. A Phase II/III Trial of Lopinavir/Ritonavir Dosed According to the Who Pediatric Weight Band Dosing Guidelines. Pediatr Infect Dis J. 2018; 37(2): e29–e35.
Reference: PAGE 30 (2022) Abstr 10102 [www.page-meeting.org/?abstract=10102]
Poster: Drug/Disease Modelling - Paediatrics