Key result
Geneva cocktail increases repaglinide exposure ~22%, validating an expanded nine-in-one phenotyping tool.
Why the study?
Clinical cocktails for cytochrome P450 phenotyping lack a marker for CYP2C8, motivating the combination of repaglinide with the Geneva cocktail and endogenous OATP1B1 and 1B3 biomarkers.
Does the addition of repaglinide to the Geneva cocktail alter the pharmacokinetics of the index drugs, and can the full cocktail accurately capture the inhibitory effects of clopidogrel and gemfibrozil?
RCT (n=16)
open-label
randomized cross-over
No
Does the addition of repaglinide to the Geneva cocktail alter the pharmacokinetics of the index drugs, and can the full cocktail accurately capture the inhibitory effects of clopidogrel and gemfibrozil?
Effect estimate: GMR 1.22 (95% CI 1.04-1.44)
Absolute Event Rate: 1.23% vs 1.01%
p-value: p=0.033
The combination of repaglinide with the Geneva cocktail and endogenous biomarkers provides a safe and effective nine-in-one phenotyping tool for seven CYP enzymes and two transporters.
Supports repaglinide addition to Geneva cocktail for multi-enzyme phenotyping; extends validation to nine-in-one CYP/transporter assessment.
Clinical cocktails for cytochrome P450 (CYP) phenotyping lack a marker for CYP2C8. We aimed to combine the CYP2C8 index drug repaglinide with the Geneva cocktail (caffeine/CYP1A2, bupropion/CYP2B6, flurbiprofen/CYP2C9, omeprazole/CYP2C19, dextromethorphan/CYP2D6, and midazolam/CYP3A4). We also included endogenous organic anion transporting polypeptide (OATP) 1B1 and 1B3 biomarkers glycochenodeoxycholate 3‐O‐glucuronide and glycochenodeoxycholate 3‐sulfate, and investigated the CYP2C8 inhibition selectivity of clopidogrel and gemfibrozil with the full cocktail. In a five‐phase randomized cross‐over study, the following drugs were administered to 16 healthy volunteers: (i) repaglinide, (ii) the Geneva cocktail, (iii) repaglinide with the Geneva cocktail (full cocktail), (iv) clopidogrel followed by the full cocktail, and (v) gemfibrozil followed by the full cocktail. The Geneva cocktail increased repaglinide AUC 0‐23h 1.22‐fold (90% confidence interval 1.04–1.44, P = 0.033). The full cocktail accurately captured known inhibitory effects of clopidogrel on CYP2B6, CYP2C8, and CYP2C19 and that of gemfibrozil on CYP2C8. Gemfibrozil decreased the paraxanthine/caffeine AUC 0‐12h ratio by 23% (14–31%, P < 0.01) and increased caffeine AUC 0‐12h 1.20‐fold (1.03–1.40, P = 0.036). Gemfibrozil increased the metabolite‐to‐index drug AUC 0‐23h ratios of flurbiprofen, omeprazole, dextromethorphan, and midazolam 1.59‐fold (1.32–1.92), 1.47‐fold (1.34–1.61), 1.79‐fold (1.23–2.59), and 2.1‐fold (1.9–2.4), respectively, without affecting the index drug AUCs ( P < 0.01). Gemfibrozil increased the AUC 0‐4h of glycochenodeoxycholate 3‐O‐glucuronide 1.33‐fold (1.07–1.65, P = 0.027). In conclusion, the combination of repaglinide, the Geneva cocktail and endogenous biomarkers for OATP1B1 and OATP1B3 yields a nine‐in‐one phenotyping tool. Apart from strong CYP2C8 inhibition, gemfibrozil weakly inhibits CYP1A2 and OATP1B1 and appears to impair the elimination of the metabolites of several CYP index drugs.
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Aurinsalo et al. (2025) conducted an RCT in healthy volunteers (n=16). Geneva cocktail + repaglinide vs. repaglinide alone was evaluated on Repaglinide AUC 0-23h (GMR 1.22, 95% CI 1.04-1.44, p=0.033). The Geneva cocktail increased repaglinide AUC 0-23h 1.22-fold compared to repaglinide alone, validating a nine-in-one phenotyping tool for CYP enzymes and transporters.
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