FDA approve lopinavir/r once daily for treatment naive patients

At the end of April, the FDA approved Kaletra at a once-daily dose (lopinavir/ritonavir 800/200mg) for treatment-naïve adult patients.

Once daily Kaletra is not approved for treatment experienced patients because trough concentrations of lopinavir are approximately 60% lower than that observed in the twice daily regimen and because there are no clinical studies comparing the two dosing schedules in treatment-experienced individuals. Once-daily Kaletra in paediatric patients has not yet been studied.

New pharmacology data

Multiple dosing of 800/200 mg Kaletra QD for 4 weeks with food (n=24) produced a mean + SD lopinavir peak plasma concentration (Cmax) of 11.8 + 3.7 ug/mL, occurring approximately 6 hours after administration. The mean steady-state trough concentration prior to the morning dose was 3.2 + 2.1 ug/mL and minimum concentration within a dosing interval was 1.7 + 1.6 ug/mL. Lopinavir Area Under the Curve (AUC) over a 24 hour dosing interval averaged 154.1 + 361.4 ug x h/mL

Increased side effects

The incidence of diarrhea was greater for once daily compared to twice daily in Study 418 (57% vs 35% – events of all grades and probably or possibly related to drug: 16% vs 5% – events of at least moderate severity and probably or possibly related to drug).

Treatment response and outcomes of randomised treatment are presented in Table 6 below.

Table 6: Treatment response and outcomes of once-daily vs twice daily LPV/r, with once-daily TDF+FTC

Outcome LPR/r QD (N=115) LPV/r BID (N=75)
Responder 71% 65%
Virologic failure 10% 9%
Rebound 6% 5%
Never <50 copies/ml 3% 4%
Death 0% 1%
D/c due to side effects 12% 7%
D/c other reasons 9% 19%

In the precautions section, Table 10: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction was revised to include information that Kaletra should not be administered once daily in combination with efavirenz, nevirapine, amprenavir, nelfinavir, carbamazepine, phenobarbital, or phenytoin. In addition, statements that Kaletra once daily has not been studied in combination with indinavir or saquinavir was included.

Additional cautions to once-daily dosing

Kaletra should not be administered as a once-daily regimen in combination with efavirenz, nevirapine, amprenavir or nelfinavir.

Source: FDA listserve, April 2005


With almost twice the rate of diarrhoea, once daily Kaletra will probably only improve quality of life in treatment naïve patients for whom once-daily regimens are essential.

It is important to remember that once-daily strictly means every 24 hours (Q24H), and that missed or late doses of Kaletra are potentially more of a concern than when dosed twice-daily, due to the lower drug trough concentration after 24 hours compared to 12 hours.

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