Crushing Kaletra tablets for kids leads to lower drug levels

Using crushed lopinavir/ritonavir (Kaletra) tablets in children with HIV because of difficulties in swallowing whole tablets should be avoided, American researchers report in the advance online edition of the Journal of Acquired Immune Deficiency Syndromes.

Brookie M Best and colleagues undertook a randomised, open-label, cross-over study comparing whole and crushed tablets and the corresponding amounts of lopinavir/ritonavir detectable in the bloodstreams of HIV-infected children.

Drug levels were reduced by an average of 40% in children who received crushed tablets, but the reduction in drug levels varied from 5% to 75% between participants in the study. Using crushed Kaletra tablets could lead to potential drug failure as well as the risk of resistance in paediatric HIV patients, the researchers observed.

Lopinavir / ritonavir (Kaletra, also marketed as Aluvia in low and middle-income countries), a co-formulated protease inhibitor (PI), is recommended as first-line therapy for the treatment of HIV in infants, children and adolescents.

Lopinavir/ritonavir is also available in liquid form for infants and young children. It has an extremely unpleasant taste “with a high content (42%) of alcohol, creating the potential for significant alcohol toxicity with overdose, especially in infants”. It also has to be taken with food and requires refrigeration so making it a poor choice in resource-poor settings.

The availability of a paediatric smaller lopinavir/ritonavir tablet (100/25mg), note the authors, has improved acceptance among children. Nonetheless, they add, within their extensive HIV paediatric practice in the United States a considerable number of children and adolescents continue to have problems in swallowing the tablets or liquid form.

The lack of availability and a guaranteed continued supply of liquid and child- sized tablets in many settings means that adult pills are the primary means of antiretroviral treatment in children. The authors note that even in areas of established access, providers hesitate in using child tablets since supply is less reliable than for adult tablets.

Swallowing an adult-sized tablet can be difficult for children and may present choking risks in young children. Caretakers faced with these difficulties will consider giving the child broken or crushed tablets.

The newer tablet form of Kaletra does not require refrigeration. Instructions clearly state that the tablet should not be crushed, broken or chewed based on studies in animals. These studies showed a 33% lower lopinavir and 61% lower ritonavir exposure in a crushed tablet compared to a whole one.

No evidence exists to support or dissuade providers from crushing tablets as a strategy for paediatric ART; no studies have been undertaken in humans on the effect of crushing tablets on drug exposure.

The authors undertook a prospective, randomised, open label, cross-over pharmacokinetic study in HIV-infected children taking Kaletra twice daily as part of their ART regimen. Eligibility included being between six and 17 years of age, having documented HIV infection and having taken Kaletra 200/50mg lopinavir/ritonavir tablets at standard paediatric doses for more than two weeks.

The children were randomised equally to study arms A and B. Arm A were given whole Kaletra tablets at the first visit and crushed tablets at the second visit. Children in Arm B got the drug in reverse order.

Study visits one and two consisted of the same procedures: Whole tablets were taken with six ounces of water. Tablets were crushed with a commercial pill crusher and mixed into four ounces of Jell-O brand pudding. Medicine remaining in the pill crusher was scraped out with a metal spatula and stirred into the pudding. Children had a standard breakfast (7 calories per kilo, 20% protein, 50% carbohydrates and 30% fat) and finished within 30 minutes of taking the drug. They ate freely throughout the day.

Blood was drawn before taking the drugs and then at 1, 2, 4, 6, 8 and 12 hours after taking the drug to measure the amount of lopinavir and ritonavir in the blood.

Twelve children aged 10-16 years of age enrolled between August 2008 and August 2009 were evaluated.

Exposure to both lopinavir and ritonavir is determined by a measure called area under the curve (AUC). Median lopinavir AUC after taking crushed and whole tablets was 92 mg*hr/l and 144 mg*hr/l, respectively with an AUC ratio of 0.55, p=0.003 and median ritonavir AUC of crushed and whole tablets was 7 mg*hr/l and 13.3 mg*hr/l respectively, with an AUC ratio of 0.53, p=0.006.

Lopinavir and ritonavir levels were thus decreased by 45% and 47%, respectively.

The authors conclude “Increased doses and therapeutic drug monitoring are needed to ensure adequate lopinavir/ritonavir exposure in patients requiring crushed Kaletra tablets. The reduced exposure with crushed Kaletra tablet dosing reinforces the need to discourage this dosing practice.”

Best BM et al. Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. JAIDS advance online edition, doi: 10.1097/QAI.0b013e318232b057, 2011.