Crushing lopinavir/ritonavir tablets decreases exposure by almost half in children

Crushing lopinavir/ritonavir (LPV/r; Kaletra) tablets is not recommended by the manufacturer as pre-clinical studies showed poor absorption with this method of administration compared to whole tablets with a single dose.

The liquid formulation of LPV/r is unpalatable and inconvenient so administrating crushed tablets could potentially overcome this barrier to the paediatric use of this PI.

As single dose pharmacokinetics (PK) do not predict steady state LPV concentrations (due to the complex interaction with ritonavair [RTV]), investigators from the Children’s National Medical Center (CMC) in Washington, DC, looked at LPV/r exposure in whole and crushed 200/50mg tablets in children. Results were published ahead of print in JAIDS.

Brookie M Best and colleagues conducted a prospective, open label, cross over PK study in 13 (6 boys, 7 girls) children and adolescents with a median age of 13 years (range 10-16) taking LPV/r tablets BID as part of their antiretroviral regimen with two NRTIs. The median LPV/r dose was 275/69mg/m2 (range 193/48-372/93mg/m2. Two participants were excluded from the analysis, one refused to take the crushed tablets, and the other had very low or undetectable levels of LPV with both methods of administration. Data are from 11 participants.

The median LPV AUC, after receiving crushed and whole tablets respectively were, 92 (IQR 79-103) mg*hr/L and 144 (IQR 101-202) mg*hr/L; crushed/whole GM 0.55 (90% CI0.45-0.69), p=0.003. The corresponding values for RTV were AUC 7(IQR 4.5 -11.1) mg*hr/L and 13.3 (IQR 9.6-17.9) mg*hr/L; GM 0.53 (90% CI 0.4-0.71), p=0.006.

Oral CL/F (L/hr/m2) was significantly increased with crushed tablets for both drugs, respectively 1.4 and 1.6 times for LPV and RTV. The maximum post dose concentrations (Cmax) were also reduced, (significantly for LPV, p=0.021) with crushed tablets.

The investigators wrote: “The reduced exposure with crushed Kaletra tablet dosing reinforces the need to discourage this practice.”

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This study was conducted prior to the introduction of the smaller tablet formulation (100/25 mg, LPV/RTV).

These data reinforce both the importance of following manufacturers instructions about dividing protease inhibitors and the need for an alternative formulation to the oral suspension. The sprinkle formulation, being developed by Cipla and studied in CHAPAS 2, is still eagerly awaited, particularly for the very young age group.

Best BM et al. Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. JAIDS. Publish ahead of print. DOI: 10.1097/QAI.0b013e318232b057.
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