Mechanism of Action

Lopinavir is an antiviral drug.

Pharmacokinetics

The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-1 infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolized by CYP3A. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration of KALETRA 400/100 mg twice-daily yields mean steady-state lopinavir plasma concentrations 15- to 20-fold higher than those of ritonavir in HIV-1 infected patients. The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice-daily.

The in vitro antiviral EC₅₀ of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of KALETRA is due to lopinavir.

Figure 1 displays the mean steady-state plasma concentrations of lopinavir and ritonavir after KALETRA 400/100 mg twice-daily with food for 3 weeks from a pharmacokinetic study in HIV-1 infected adult subjects (n = 19).

Figure 1. Mean Steady-state Plasma Concentrations with 95% Confidence Intervals (CI) for HIV-1 Infected Adult Subjects (N = 19)

Absorption

In a pharmacokinetic study in HIV-1 positive subjects (n = 19), multiple dosing with 400/100 mg KALETRA twice-daily with food for 3 weeks produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 9.8 ± 3.7 μg/mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1 ± 2.9 μg/mL and minimum concentration within a dosing interval was 5.5 ± 2.7 μg/mL. Lopinavir AUC over a 12 hour dosing interval averaged 92.6 ± 36.7 μg•h/mL. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established. Under nonfasting conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of KALETRA co-formulated capsules and oral solution. When administered under fasting conditions, both the mean AUC and Cmax of lopinavir were 22% lower for the KALETRA oral solution relative to the capsule formulation.

Plasma concentrations of lopinavir and ritonavir after administration of two 200/50 mg KALETRA tablets are similar to three 133.3/33.3 mg KALETRA capsules under fed conditions with less pharmacokinetic variability.

Effects of Food on Oral Absorption

KALETRA Tablets

No clinically significant changes in Cmax and AUC were observed following administration of KALETRA tablets under fed conditions compared to fasted conditions. Relative to fasting, administration of KALETRA tablets with a moderate fat meal (500 - 682 Kcal, 23 to 25% calories from fat) increased lopinavir AUC and Cmax by 26.9% and 17.6%, respectively. Relative to fasting, administration of KALETRA tablets with a high fat meal (872 Kcal, 56% from fat) increased lopinavir AUC by 18.9% but not Cmax. Therefore, KALETRA tablets may be taken with or without food.

KALETRA Oral Solution

Relative to fasting, administration of KALETRA oral solution with a moderate fat meal (500 - 682 Kcal, 23 to 25% calories from fat) increased lopinavir AUC and Cmax by 80 and 54%, respectively. Relative to fasting, administration of KALETRA oral solution with a high fat meal (872 Kcal, 56% from fat) increased lopinavir AUC and Cmax by 130% and 56%, respectively. To enhance bioavailability and minimize pharmacokinetic variability KALETRA oral solution should be taken with food.

Distribution

At steady state, lopinavir is approximately 98-99% bound to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin; however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg KALETRA twice-daily, and is similar between healthy volunteers and HIV-1 positive patients.

Metabolism

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