Poster Presentation [PDF | 271 KB]

Simulation and Exposure-Based Assessment of Pediatric Lopinavir Fixed-Dose Combination Product

Saïk Urien [1-3], Naïm Bouazza [1-3], Frantz Foissac [1-3], Floris Fauchet [1-3],  David Burger [4], Jean-René Kiechel [5], Edmund Capparelli [6], Jean Marc Treluyer  [1-3], Marc Lallemant [5]

1. Université Paris Descartes, Sorbonne, Paris, France
2. Unité de Recherche clinique, Assistance Publique – Hôpitaux de Paris (AP-HP), Hôpital Tarnier, Paris
3. Inserm, Cochin-Necker, Paris
4. Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands
5. Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland
6. University of California, San Diego, La Jolla, CA, USA

Poster Session Title: ARV Pharmacokinetics, Pharmacogenetics, and Safety in Children and Adolescents
Tuesday, March 4, 2:30-4:00 PM
Poster Hall
Poster Board Number: 907

Abstract:

Background: The development of low-cost, solid fixed-dose combinations of LPV/r with various nucleoside reverse transcriptase inhibitor (NRTI) backbones in modular unit forms (LPV/ABC/3TC and LPV/ZDV/3TC) is greatly needed to improve both management and adherence of children especially in resource-limited settings.

Methods: The pharmacokinetic (PK) analysis combined 25 datasets including therapeutic drug monitoring and published clinical studies from IMPAACT and PENTA. Intensive and sparse PK data totaling 1394 LPV concentrations from 338 subjects, aged 2 days to 24 years old, were analysed. For 3TC, ABC, and ZDV, a total of 927 patients with 3820 concentrations, 188 patients with 1232 concentrations, and 756 patients with 3312 concentrations were used, respectively.

Results: The simulations indicated that the WHO dosing recommendations resulted in more than 95% of subjects with LPV Cmin >1.0 mg/L. However, using the recommended drug ratios, the combination dosage for the 4-6 kg weight band (LPV/ZDV: 120/90mg BID) resulted in high ZDV exposure with more than 20% of subjects at levels associated with high risk of neutropenia (Cave>0.8 mg/L). Reducing the LPV/ZDV dosage to 80/60 mg BID significantly decreased frequency of high ZDV concentrations and risk of neutropenia. This dosage reduction retained LPV Cmin >1.0 mg/L in more than 95% of subjects and did not adversely affect reaching the NRTIs therapeutic target levels. Moreover, this proposed dosage fully corresponded to the WHO guidelines for all NRTIs.

Conclusions: These simulations suggest that a pediatric fixed-dose LPV/3TC/ZDV or ABC formulation could be developed to achieve targeted therapeutic levels for all ARV components. Each unit would include 40 mg LPV, 10 mg RTV, 15 mg 3TC and 30 mg ABC or ZDV.  According to the weight bands, i.e. 4-6 kg, 6-10 kg, 10-14 kg, 14-20 kg, 20-25 kg, therapeutic doses would be 2, 3, 4, 5, or 6 units twice daily of this formulation.