Drug Interactions between lopinavir / ritonavir and quinine

ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.

ADJUST DOSING INTERVAL: Food significantly increases the bioavailability of lopinavir from the oral solution formulation of lopinavir-ritonavir. Relative to fasting, administration of lopinavir-ritonavir oral solution with a moderate-fat meal (500 to 682 Kcal; 23% to 25% calories from fat) increased lopinavir peak plasma concentration (Cmax) and systemic exposure (AUC) by 54% and 80%, respectively, whereas administration with a high-fat meal (872 Kcal; 56% from fat) increased lopinavir Cmax and AUC by 56% and 130%, respectively. No clinically significant changes in Cmax and AUC were observed following administration of lopinavir-ritonavir tablets under fed conditions versus fasted conditions. Relative to fasting, administration of a single 400 mg-100 mg dose (two 200 mg-50 mg tablets) with a moderate-fat meal (558 Kcal; 24.1% calories from fat) increased lopinavir Cmax and AUC by 17.6% and 26.9%, respectively, while administration with a high-fat meal (998 Kcal; 51.3% from fat) increased lopinavir AUC by 18.9% but not Cmax. Relative to fasting, ritonavir Cmax and AUC also increased by 4.9% and 14.9%, respectively, with the moderate-fat meal and 10.3% and 23.9%, respectively, with the high-fat meal.

MANAGEMENT: Lopinavir-ritonavir oral solution should be taken with meals to enhance bioavailability and minimize pharmacokinetic variability. Lopinavir-ritonavir tablets may be taken without regard to meals.

Coadministration with grapefruit juice does not appear to affect the pharmacokinetics of quinine in a clinically relevant manner. Although grapefruit juice is an inhibitor of CYP450 3A4 and quinine is metabolized by this pathway to its major metabolite, 3-hydroxyquinine, a study of ten healthy volunteers found no significant differences in quinine peak plasma concentration (Cmax), time to reach Cmax (Tmax), terminal elimination half-life, systemic exposure (AUC), or apparent oral clearance (Cl/F) when a single 600 mg oral dose of quinine sulfate was administered in combination with 200 mL of orange juice (control), half-strength grapefruit juice, and full-strength grapefruit juice twice daily for 6 days each, separated by a 2-week washout period. Relative to the control period, the apparent renal clearance of quinine was markedly increased by 81% during treatment with half-strength grapefruit juice. However, since renal clearance accounts for approximately 6% of the total clearance of quinine, this change would likely have minimal clinical impact. The lack of a significant interaction is probably due to the fact that grapefruit juice primarily inhibits intestinal rather than hepatic CYP450 3A4, and quinine is not known to undergo significant presystemic metabolism as evidenced by its relatively high oral bioavailability (76% to 88%). Nevertheless, excessive consumption of grapefruit juice and tonic water (which contains quinine) was suspected as the cause of torsade de pointes arrhythmia in a patient with a history of asymptomatic long QT syndrome. Treatment with magnesium sulfate and metoprolol had no effect, but the arrhythmia resolved spontaneously 48 hours after discontinuation of the drinks. Based on current data, moderate grapefruit juice consumption is probably safe for the majority of patients taking quinine.