Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children
Brookie M Best1, Edmund V Capparelli, Huy Diep
1Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0719, USA. brookie@ucsd.edu
Insights
Crushing lopinavir/ritonavir (Kaletra) tablets for pediatric HIV patients significantly reduces drug exposure by approximately 45%. This practice necessitates dose adjustments and therapeutic drug monitoring, and ideally should be avoided.
Area of Science:
- Pharmacology and Therapeutics
- Pediatric Infectious Diseases
- HIV/AIDS Treatment
Background:
- Lopinavir/ritonavir (Kaletra) is a first-line antiretroviral therapy for pediatric HIV infection.
- In clinical settings, Kaletra tablets are sometimes crushed for easier administration to children.
- The impact of crushing tablets on drug exposure in pediatric patients is not well-established.
Purpose of the Study:
- To compare the pharmacokinetic exposure of lopinavir/ritonavir when administered as whole versus crushed tablets in HIV-infected children.
- To determine the extent of reduction in drug exposure due to tablet crushing.
- To inform clinical practice regarding the administration of lopinavir/ritonavir in pediatric populations.
Main Methods:
- A randomized, open-label, cross-over study design was employed.
- Pediatric patients receiving lopinavir/ritonavir underwent two 12-hour pharmacokinetic studies within 30 days: one with whole tablets and one with crushed tablets.
- Plasma concentrations of lopinavir and ritonavir were measured, and pharmacokinetic parameters including area under the curve (AUC) were calculated and compared using Wilcoxon signed-rank tests.
Main Results:
- Twelve children (median age 13 years) participated in the study.
- Crushing tablets resulted in a significant reduction in drug exposure: median lopinavir AUC decreased by 45% (AUC ratio 0.55, P=0.003) and median ritonavir AUC decreased by 47% (AUC ratio 0.53, P=0.006).
- The median doses administered were 550/138 mg·m(-2) per day, divided every 12 hours.
Conclusions:
- Administering crushed lopinavir/ritonavir tablets significantly reduces exposure to both lopinavir and ritonavir in children.
- To achieve therapeutic drug levels, higher doses and therapeutic drug monitoring would be required when using crushed tablets.
- The use of crushed lopinavir/ritonavir tablets should be avoided whenever possible to ensure treatment efficacy.
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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