Clinically relevant enantiomer specific R‐ and S‐praziquantel pharmacokinetic drug‐drug interactions with efavirenz and ritonavir. Issue 3 (30th April 2021)

• Record Type: Journal Article
• Authors: Mutiti, Chenai Sheilla; Kapungu, Nyasha Nicole; Kanji, Comfort Ropafadzo; Stadler, Nadina; Stingl, Julia; Nhachi, Charles; Hakim, James; Masimirembwa, Collen; Thelingwani, Roslyn Stella
• Is Part Of: Pharmacology research & perspectives. Volume 9:Issue 3(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-04-30
• Subjects: drug‐drug interaction -- enantiomer specific -- pharmacokinetics -- praziquantel; Pharmacology -- Periodicals; Drug development -- Periodicals; 615.105
• DOI: 10.1002/prp2.769
• Languages: English
• ISSNs: 2052-1707

Abstract

Abstract: We conducted a clinical study to determine the effect of efavirenz and ritonavir on the pharmacokinetics of R‐ and S‐PZQ in healthy male participants. This was toward evaluating the risk of drug‐drug interactions, which may occur after PZQ administration to HIV patients on efavirenz or ritonavir containing regimens. A non‐randomized, open‐label, single‐dose, one sequence crossover study with 2 arms was conducted. We gave 26 healthy volunteers a single oral dose of 40 mg/kg PZQ followed by a daily oral dose of either 400 mg efavirenz or 100 mg ritonavir for 14 consecutive days. On day 14, they ingested a single 40 mg/kg dose of PZQ. We measured plasma levels up to 12 h on day 1 and day 14. Samples were analyzed by LC‐MS. Pharmacokinetic analysis was conducted in WinNonlin to determine the primary endpoints (plasma T 1/2, C min, and AUC). Efavirenz had a significant effect on the pharmacokinetics of PZQ ( p < .05), reducing the AUC by 4‐fold (1213.15 vs. 281.35 h·ng/ml for R‐PZQ and 5669 vs. 871.84 h·ng/ml for S‐PZQ). Ritonavir had no significant effect on R‐PZQ but increased the AUC 2‐fold for S‐PZQ ( p < .05) (4154.79 vs. 7291.05 h·ng/ml). Using PZQ in HIV patients needs investigation, as there is a risk of both treatment failure and adverse effects because of induction and inhibition, respectively. Abstract : The effect of efavirenz and ritonavir on the pharmacokinetics of praziquantel (PZQ) were investigated. An open label, single dose one sequence crossover clinical study with 26 healthy male volunteers was conducted. Efavirenz decreased the AUC of PZQ 4‐fold ( p < .05) whereas ritonavir increased the AUC 2‐fold. There was no significant change in the T max and t 1/2 suggesting prolongation of absorption and a significant role of hepatic metabolism as compared to gut metabolism. Co‐administration of efavirenz and praziquantel is very likely to cause clinically relevant drug‐drug interactions where praziquantel falls below the minimum effective concentration (MEC) of 1 μg/ml which should be maintained for at least 4 h. This should be considered when treating schistosomiasis in infected HIV patients on efavirenz containing regimens with praziquantel.