Paper # 877 
Pharmacokinetics of Lopinavir/Ritonavir Crushed vs Whole Tablets in Children
H Diep1, Brookie Best*1, E Capparelli1, S Rossi1, M Farrell1, E Williams2, G Lee2, J van den Anker2, and N Rakhmanina2
1Univ of California, San Diego, US and 2Children’s Natl Med Ctr, Washington, DC, US
Background: Lopinavir/ritonavir (LPV/RTV) is a
first-line co-formulated protease inhibitor for treatment of HIV infection. A
200/50 mg tablet LPV/RTV is widely used; according to the manufacturer, it
may not be crushed. However, caregivers report dosing pediatric patients with
crushed tablets. LPV/RTV pharmacokinetics (PK) after crushed tablet
administration needs to be determined.
Methods: This was a randomized, open-label,
cross-over study of pediatric subjects who were taking LPV/RTV > 4 weeks.
Subjects had 2 separate 12 hrs PK studies following an observed dose of LPV/RTV
400/100 mg of either crushed or whole tablets. Blood samples were drawn at 0
(pre-dose), 1, 2, 4, 6, 8, and 12 hours. Plasma concentrations of LPV and RTV
measured by HPLC were used to calculate non-compartmental area under the curves
(AUC) and clearances (CL/F). Wilcoxon signed-rank tests compared medians of PK
values between crushed and whole tablets.
Results: Thirteen patients enrolled, 12 completed
the study (5 males/7 females). One patient was averse to the crushed tablet
texture, refused to take that dose, and was replaced. Median age was 13 (9 to 16)
years. LPV/RTV concentrations were below detection pre-dose at 7 PK visits. LPV
and RTV PK parameters are presented in the table below as ratios (90%
Confidence Interval) and in the figures as median concentrations.
|
|
LPV
|
RTV
|
|
|
Ratio of Crushed/Whole
|
Ratio of Crushed/Whole
|
|
AUC0-12
(mcg.h/mL)
|
0.60*
(0.48-0.72)
|
0.61*
(0.45-0.77)
|
|
CL/F (L/h)
|
1.96
(1.52-2.41)
|
2.21*
(1.56-2.86)
|
|
C12 (mcg/mL)
|
0.67*
(0.48-0.86)
|
0.97
(0.75-1.19)
|
|
Cmax (mcg/mL)
|
0.81*
(0.65-0.98)
|
0.86
(0.54-1.19)
|
*p<0.05 for comparison of crushed to whole tablets
 
Conclusions: Administration of a single dose of
crushed 200/50 mg LPV/RTV tablets to pediatric patients led to a significant
reduction in AUC of LPV and RTV by 40% and 39%, respectively. Administration of
crushed LPV/RTV tablets produces low LPV exposure and is not recommended.
Therapeutic drug monitoring to ensure adequate exposure is warranted in
patients reporting crushing the LPV/RTV tablets. PK of LPV/RTV at steady-state
after multiple crushed tablet doses requires further investigation.
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