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Randomized Controlled Trial
. 2011 Dec 1;58(4):385-91.
doi: 10.1097/QAI.0b013e318232b057.

Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children

Brookie M Best  1 , Edmund V Capparelli, Huy Diep, Steven S Rossi, Michael J Farrell, Elaine Williams, Grace Lee, John N van den Anker, Natella Rakhmanina
Affiliations
Randomized Controlled Trial

Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children

Brookie M Best et al. J Acquir Immune Defic Syndr. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest: All authors have no personal or financial relationships that might bias this work.

Figures

Figure 1
Figure 1. Median lopinavir concentrations with whole and crushed tablets
Median lopinavir concentration-time curves in patients after administration of whole tablets (solid line, n=11) and crushed tablets (dotted line, n = 11).
Figure 2
Figure 2. Median ritonavir concentrations with whole and crushed tablets
Median ritonavir concentration-time curves in patients after administration of whole tablets (solid line, n=11) and crushed tablets (dotted line, n = 11).
Figure 3
Figure 3. Lopinavir AUC with whole tablets vs. crushed tablets
Changes in lopinavir AUC from whole tablets (left column) to crushed tablets (right column) in the same patients (n=12). The dotted line represents the typical lopinavir AUC of approximately 97 mcg*hr/mL in adult patients following administration of two 200mg/500mg lopinavir/ritonavir tablets.
Figure 4
Figure 4. Ritonavir AUC with whole tablets vs. crushed tablets
Changes in ritonavir AUC from whole tablets (left column) to crushed tablets (right column) in the same patients (n=12).
See this image and copyright information in PMC

References

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    1. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. [Accessed January 01, 2011];Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Updated August 16, 2010. Available at http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf.
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