Objectives: Primary objective: Evaluation of the effect of the proton pump inhibitor (PPI) pantoprazole on the absorption of hydroxychloroquine (HCQ). Secondary objectives:• Evaluation of the relationship between HCQ concentrations in whole blood, plasma and intracellular concentrations in target cells -peripheral blood mononuclear cells (PBMCs).• Evaluation of HCQ as a potential perpetrator in drug-drug interactions at the level of cytochrome P450 (CYP) 3A4 and CYP2D6 (major drug metabolizing enzymes). Trial design:Single centre, open-label, parallel group, two-arm, phase I drug-drug interaction trial.
Hydroxychloroquine as a weak basic compound with two amines is strongly enriched in cell compartments with low pH, suggesting that modification of gastric pH by coadministered proton pump inhibitors might reduce its solubility and absorption and thus its efficacy in patients. We addressed this question in a single-center, open-label, randomized, parallel drug-drug interaction trial in healthy adults (EudraCT No. 2020-001470-30). All participants received a single oral dose of 400-mg hydroxychloroquine, and one group additionally received 40 mg of pantoprazole once daily for 9 days dosed to steady state. Whole-blood samples were collected for 72 hours, and hydroxychloroquine was quantified by liquid chromatography-tandem mass spectrometry. Primary endpoints were whole-blood hydroxychloroquine areas under the concentration-time curve from 0 to 72 hours (AUC 0-72h ) and peak concentrations (C max ). Unpaired 2-sided t-tests of the log transformed pharmacokinetic parameters were performed to compare both groups. Twenty-four participants (12 per group) were included. Hydroxychloroquine AUC 0-72h and C max did not differ between groups without and with pantoprazole (arithmetic mean; AUC 0-72h , 7649 ng/ml • h, and 8429 ng/ml • h, P = .50; C max , 448 ng/mL and 451.5 ng/mL, P = .96, respectively). Pantoprazole did not alter hydroxychloroquine absorption, indicating that proton pump inhibitors do not affect its bioavailability.
Background and Objective Voriconazole is an important broad-spectrum anti-fungal drug with nonlinear pharmacokinetics. The aim of this single centre fixed-sequence open-label drug–drug interaction trial in healthy participants ( N = 17) was to determine whether microdosed probe drugs for CYP3A and CYP2C19 reliably predict voriconazole clearance (CL VRZ ). Methods At baseline, a single oral microdose of the paradigm substrates midazolam (CYP3A) and omeprazole (CYP2C19) were given to estimate their clearances (CL). Thereafter, a single oral dose of voriconazole was administered (50, 100, 200 or 400 mg), followed by the microdosed probe drugs. Results The clearances of midazolam (CL MDZ 790–2790 mL/min at baseline; 248–1316 mL/min during voriconazole) and omeprazole (CL OMZ 66.4–2710 mL/min at baseline; 30.1–1420 mL/min during voriconazole) were highly variable. CL MDZ [geometric mean ratio (GMR) 0.586 at 50 mg voriconazole decreasing to GMR 0.196 at 400 mg voriconazole] and CL OMZ (GMR 0.590 at 50 mg decreasing to GMR 0.166 at 400 mg) were reduced with higher voriconazole doses. CL MDZ was linearly correlated with CL VRZ (slope 1.458; adjusted R 2 0.528) as was CL OMZ (slope 0.807; adjusted R 2 0.898). Multiple linear regression resulted in an adjusted R 2 of 0.997 for the relationship CL VRZ ~ log CL OMZ + log CL MDZ using data during voriconazole treatment and an adjusted R 2 of 0.997 for the relationship CL VRZ ~ log CL OMZ + log CL MDZ + voriconazole dose, using baseline data for CL MDZ and CL OMZ . Conclusion Microdosed midazolam and omeprazole accurately described and predicted total CL VRZ Trial Registration EudraCT No: 2020-001017-20, registered on March 5th, 2020. DRKS: DRKS00022547, registered on August 6th, 2020. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-01287-7.
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