Does CYP3A4*1B change midazolam pharmacokinetics in preterm infants?

The CYP3A4*1B mutation may be associated with altered CYP3A activity in adults. The CYP3A4 substrate midazolam (M) shows large interindividual PK differences in neonates. Thus, we studied the effect of CYP3A4*1B on M PK in preterm neonates. Methods: M (0.1 mg/kg) was administered as an oral bolus dose to 15 preterm infants (GA 26-34 wks, 3-13 days old, 11 Caucasians, 1 Mediterranean and 2 Caribbean Africans) followed by repeated blood sampling over 24 hrs. M and 1OHM concentrations were determined using GC-ELD; PK was determined with non compartmental analysis. CYP3A4*1B mutation analysis was carried out with PCR-RFLP. Results: M AUC_0-∞ was significantly (p=0.043, Mann-Whitney test) lower in patients with the CYP3A4*1B genotype (1 A/G, 2 GG) compared to wildtype (12 A/A). M Cl/F (L/kg/h) was also increased, although not significantly (p=0.06) in the CYP3A4*1B carriers. Conclusions: The CYP3A4*1B appears to be associated with increased oral M clearance, which may reflect increased intestinal and/or hepatic CYP3A4 activity in preterm infants carrying the *1B allele.