Pharmacokinetics of Lopinavir/Ritonavir: Changes Across Formulations and Ages

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

References

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
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.