Pharmacokinetics of Lopinavir/Ritonavir Crushed Versus Whole Tablets in Children

Objective: Lopinavir/ritonavir (Kaletra) is first-line therapy for pediatric HIV infection. In clinical practice, Kaletra tablets are occasionally crushed for pediatric administration. This study compared lopinavir/ritonavir exposure between whole and crushed tablets in HIV-infected children. Design: This was a randomized, open-label, cross-over study of pediatric patients taking lopinavir/ritonavir as part of their antiretroviral regimen. Each subject had 2 separate (within 30 days) steady-state 12-hour pharmacokinetic (PK) studies with crushed and whole 200/50 mg lopinavir/ritonavir tablets. Methods: PK blood samples were drawn at 0 (predose), 1, 2, 4, 6, 8, and 12 hours postdose. Lopinavir and ritonavir plasma concentrations measured by high-performance liquid chromatography were used to calculate non-compartmental area under the concentration versus time curve (AUC) and clearance. Wilcoxon signed-rank tests compared PK values between crushed and whole tablets. Results: Twelve children, median age of 13 years (10-16 years), took 550/138 mg.m(-2) per day lopinavir/ritonavir divided every 12 hours. The median lopinavir AUC after crushed and whole tablets were 92 mg.hr.L-1 and 144 mg.hr.L-1, respectively, with an AUC ratio of 0.55 (P = 0.003). Median ritonavir AUC of crushed and whole tablets were 7 mg.hr.L-1 and 13.3 mg.hr.L-1, respectively, with an AUC ratio of 0.53 (P = 0.006). Conclusions: Administration of crushed 200/50 mg lopinavir/ritonavir tablets to children significantly reduced lopinavir and ritonavir exposure with a decrease in AUC by 45% and 47%, respectively. The administration of crushed tablets would require higher doses and therapeutic drug monitoring to ensure adequate lopinavir exposure in patients requiring this practice. The use of crushed lopinavir/ritonavir tablets should be avoided, if possible.