Darunavir + Artemether/Lumefantrine = Precautionary

Effect on Concentration

Darunavir
No change
Applies within class?
No
Artemether/Lumefantrine
Decrease
Applies within class?
No

Pharmacologic Effects

Darunavir
Effect
N/A
Applies within class?
No
Artemether/Lumefantrine
Effect
N/A
Applies within class?
No

Interaction History

N/A

Last Updated 17-Jul-2018

Summary

Sources

Darunavir versus Artemether/Lumefantrine ^

Study Design

In a single-center, randomized, two-way, two-period cross-over study, 16 healthy volunteers divided into two groups; treatment sequence AB and BA. The AB group (n=8) received treatment A followed by treatment B with a washout period of 4 weeks; the BA group (n=8) received treatment B followed by treatment A with a washout period of 4 weeks. treatment A: artemether/lumefantrine 80/480 mg alone for 3 days (6 doses of 4 tablets [20/120 mg] at 0, 8, 24, 36, 48, and 60h) treatment B: Darunavir/ritonavir (DRV/r) 600/100 mg twice daily for 21 days (Day 1 to 21) with artemether/lumefantrine 80/480 mg (6 doses of 4 tablets [20/120 mg] at 0, 8, 24, 36, 48, and 60h) on Day 8 to 11, then single dose of DRV/r 600/100 mg twice daily in the morning on Day 22.

Study Results

Concomitant use of ritonavir-boosted darunavir (DRV/r) and artemether/lumefantrine in healthy individuals decreased the maximum concentration (Cmax) and AUC of both artemether and active metabolite of artemether, dihydroartemisinin (DHA). Geometric mean ratios (GMRs; DRV/r + artemether/lumefantrine / artemether/lumefantrine) [90% CIs] of AUC and Cmax for artemether were 0.84 [0.69, 1.02] and 0.82 [0.61,1.11], respectively; GMRs (DRV/r + artemether/lumefantrine / artemether/lumefantrine) [90% CIs] of AUC and Cmax for DHA were 0.82 [0.74,0.91] and 0.82 [0.66,1.01], respectively. DRV/r administration increased the AUC of lumefantrine approximately 3 fold; GMRs (DRV/r+ artemether/lumefantrine / artemether/lumefantrine) [90% CIs] of AUC for lumefantrine was 2.75 [2.46,3.08]. Artemether/lumefantrine administration did not have a clinically important effect on DRV/r plasma concentrations or AUC; GMRs (DRV/r + artemether/lumefantrine / DRV/r) [90% CIs] of AUC and Cmax for DRV/r were 0.96 [0.90,1.03] and 1.00 [0.93,1.07], respectively.

Study Conclusions

Concomitant use of artemether/lumefantrine and DRV/r decreases plasma concentrations and AUC of both artemether and active metabolite of artemether.1,2 Since the clinical significance is unknown whether the decreased artemether or DHA exposure affects antimalarial efficacy, closely monitor antimalarial efficacy of artemether/lumefantrine.3 Additionally, patients should be monitored for QTc interval prolongation as statistically significant increase in lumefantrine exposure may increase the risk of QT interval prolongation.1 Dosage adjustment for DRV is not needed as concomitant use of these two drugs does not have a clinically important effect on DRV plasma concentration or AUC.

References

Demasi R, Van delft Y, Mohammed P. Pharmacokinetic interaction between etravirine or darunavir/ritonavir and artemether/lumefantrine in healthy volunteers: a two-panel, two-way, two-period, randomized trial. Hiv Medicine. 2013; 7: 421-429.