Steady state pharmacokinetic study of FLAGYL® ER in pregnant patients during the second to third trimester of pregnancy

Purpose To compare the steady-state pharmacokinetics (PK) of oral metronidazole in pregnant and non-pregnant women requiring treatment for bacterial vaginosis (BV). Methods In an open-label, multi-centered study, 27 non-pregnant and 21 pregnant women between 17 - 27 weeks' gestation with BV received metronidazole extended release, 750 mg, once daily for 7 days. Blood and urine samples were collected on Days 6-8 for metronidazole and 2-hydroxy metronidazole levels. On Days 8 and 35–39, patients were evaluated for BV status and safety. Results Twenty pregnant and 25 non-pregnant women completed the PK analysis. Mean Cmax was significantly lower in pregnant women (8.20 μg/mL + 3.59 vs 11.08 + 3.91; P=0.019). Mean metronidazole AUC was also smaller in pregnant women with a difference that approached significance (136.22 (μg/mL)*hr + 60.57 vs. 179.55 + 75.4; P=0.057). Total oral metronidazole clearance was significantly greater in the pregnant group (P=0.043). There were no differences between renal and non-renal metronidazole clearances; however, renal clearance of 2-hydroxy metronidazole was significantly greater in pregnant women (P=0.0003). Of the women who were Nugent positive for BV, 12 of 17 pregnant women (70.6%) and 10 of 25 non-pregnant women (40.0%) were Nugent negative on Day 35. Study drug was well tolerated by both groups. Conclusions Metronidazole levels are reduced in pregnancy through possible increased CYP3A4 conversion of metronidazole to its hydroxy metabolite; however, dosage adjustments are not required to maintain efficacy. Clinical Pharmacology & Therapeutics (2004) 75, P24–P24; doi: 10.1016/j.clpt.2003.11.091