Pharmacokinetics of Lopinavir/Ritonavir: Changes Across Formulations and Ages
Higher lopinavir/ritonavir doses may be required in infants younger than 6 months of age. This is consistent with the observation that younger infants have slower viral decline after ART.
Although dosing recommendations for lopinavir/ritonavir include larger doses for infants to account for higher apparent clearance, data demonstrate that this may still result in low lopinavir concentrations for infants younger than 6 months receiving the liquid formulation, according to a population pharmacokinetic analysis published in the Journal of Clinical Pharmacology.1
Lopinavir is recommended as part of a first-line antiretroviral regimen in pediatric patients, and is available in a liquid formulation that may be used in infants as young as 2 weeks of age.2 Ritonavir is a pharmacokinetic enhancer and is coformulated with lopinavir in 3 distinct formulations: liquid, soft gel capsule, and melt-extrusion tablet. Although there are several studies that describe lopinavir/ritonavir pharmacokinetics in adults and children,3-10 no studies have described the dynamic changes that occur with lopinavir/ritonavir from infancy to adulthood.
Therefore, researchers performed a composite population pharmacokinetic analysis using 6 pediatric and adult studies performed in 297 patients aged 6 weeks to 63 years receiving the 3 different formulations.1 They found that when using the World Health Organization weight-band dosing recommendations, patients younger than 6 months had a lower area under the drug concentration-time curve (94.8 vs >107.4 µg hour/mL) and minimum observed concentration of drug in blood plasma values (5.0 vs >7.1 µg/mL) compared with older children and adults. In addition, an increase in bioavailability was observed with the transition from liquid to tablet formulation.
The researchers concluded that "the [World Health Organization] weight-band dosing simulation shows potential for low [lopinavir] concentration in early infancy with currently recommended dosing and may require further evaluation for improved dosing recommendations adjusted for newly available [lopinavir/ritonavir] pediatric formulations such as sprinkles."1
- Yang J, Nikanjam M, Best BM, et al. Population pharmacokinetics of lopinavir/ritonavir: changes across formulations and human development from infancy through adulthood [published online September 25, 2018]. J Clin Pharmacol. doi: 10.1002/jcph.1293
- National Institutes of Health Guidelines for the use of antiretroviral agents in pediatric HIV infection. https://aidsinfo.nih.gov/contentfiles/lvguidelines/PedARV_TablesOnly.pdf. Accessed January 2, 2018.
- Dickinson L, Boffito M, Back D, et al. Sequential population pharmacokinetic modeling of lopinavir and ritonavir in healthy volunteers and assessment of different dosing strategies. Antimicrob Agents Chemother. 2011;55(6):2775-2782.
- Molto J, Barbanoj MJ, Miranda C, et al. Simultaneous population pharmacokinetic model for lopinavir and ritonavir in HIV-infected adults. Clin Pharmacokinet. 2008;47(10):681-692.
- Crommentuyn KM, Kappelhoff BS, Mulder JW, et al. Population pharmacokinetics of lopinavir in combination with ritonavir in HIV-1-infected patients. Br J Clin Pharmacol. 2005;60(4):378-389.
- Jullien V, Urien S, Hirt D, et al. Population analysis of weight-, age-, and sex-related differences in the pharmacokinetics of lopinavir in children from birth to 18 years. Antimicrob Agents Chemother. 2006;50(11):3548-3555.
- Nikanjam M, Chadwick EG, Robbins B, et al. Assessment of lopinavir pharmacokinetics with respect to developmental changes in infants and the impact on weight band–based dosing. Clin Pharmacol Ther. 2012;91(2):243-249.
- Bastiaans DE, Forcat S, Lyall H, et al. Pharmacokinetics of pediatric lopinavir/ritonavir tablets in children when administered twice daily according to FDA weight bands. Pediatr Infect Dis J. 2014;33(3):301-305.
- Lopez Aspiroz E, Santos Buelga D, Cabrera Figueroa S, et al. Population pharmacokinetics of lopinavir/ritonavir (Kaletra) in HIV-infected patients. Ther Drug Monit. 2011;33(5):573-582.
- Rakhmanina N, van den Anker J, Baghdassarian A, Soldin S, Williams K, Neely MN. Population pharmacokinetics of lopinavir predict suboptimal therapeutic concentrations in treatment-experienced human immunodeficiency virus-infected children. Antimicrob Agents Chemother. 2009;53(6):2532-2538.