Influence of Rifampicin on the Pharmacokinetics of the Glucokinase Activator Globalagliatin: A Single‐Center, Open‐Label, Fixed‐Sequence Investigation in Healthy Chinese Volunteers

Objective: The orally bioavailable glucokinase activator, globalagliatin, is used to improve glucose homeostasis. Its metabolism is primarily dependent on cytochrome P450 (CYP) 3A4. Here, the influence of rifampicin, a potent inducer of CYP3A4 and CYP2C19 inducer, moderate inducer of CYP1A2, CYP2B6, CYP2C8, and CYP2C9, and inhibitor of P‐gp, on the pharmacokinetics of globalagliatin, were investigated in healthy Chinese subjects. Methods: This single‐center, open‐label, one‐sequence investigation was performed over 22 days in 24 healthy Chinese volunteers. The volunteers were given single oral doses of 80 mg of globalagliatin on Days 1 and 15 on an empty stomach, while rifampicin 600 mg was given orally once a day from Days 8–21 before breakfast. Blood samples were collected at 0 h (1 h before globalagliatin administration on Days 1 and 15) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, and 168 h after dosing to monitor the globalagliatin pharmacokinetic parameters. Blood samples on Day 8 were collected before rifampicin administration. The plasma levels of globalagliatin were assessed using LC‐MS/MS. Pharmacokinetic parameters were calculated using Phoenix WinNonlin Version 8.3.3 and analyzed with SAS Version 9.4. Continuous monitoring was performed to assess drug safety and tolerance. Results: Analysis of the effect of rifampicin on globalagliatin pharmacokinetics in 24 healthy participants showed that with rifampicin, the C max of globalagliatin decreased by 88.9%, while the AUC 0–t and AUC 0–∞ values were reduced by 97.0% and 96.4%, respectively. The geometric mean ratios of globalagliatin C max , AUC 0–t , and AUC 0–∞ and their 90% CI values were 11.09% (90% CI:9.40–13.10%), 2.96% (90% CI:2.59–3.39%), and 3.60% (90% CI:3.20–4.04%), respectively. The mean elimination half‐life was reduced by 27.91 h, while T max was prolonged by 3.52 h. Six treatment‐related adverse events were reported by five subjects (20.8%), with all being of Grade 1 severity. Conclusions: Cotreatment with rifampicin significantly reduces the plasma levels of globalagliatin. The safety and tolerability of globalagliatin, both as monotherapy and in combination with rifampicin, were good in healthy Chinese volunteers. Trial Registration: Chinese Clinical Trial Register: CTR20210959