Interim analysis, a tool to enhance efficiency of pharmacokinetic studies: Pharmacokinetics of rifampicin in lactating mother-infant pairs

Abstract

Pharmacokinetic studies are important for understanding drug disposition in the human body. However, pregnant and lactating women are often excluded from primary pharmacokinetic studies and as such there is often limited dosing information regarding drug use in pregnant and/or lactating women. The objectives of this interim analysis were to define the transfer of rifampicin to a breastfed infant and to determine the area under the concentration-time curve of rifampicin in maternal plasma, breastmilk and infant plasma. Performing this interim analysis enabled us to substantiate whether prior assumptions we made on several study design issues including patient sample size and pharmacokinetic sampling times held and whether we needed to amend our protocol or not. We enrolled lactating mothers on treatment for tuberculosis with their breastfeeding infants (below 12 months of age), performed intensive pharmacokinetic sampling (0-24 h post-dose) on plasma samples from both the mother, infant(s) and breastmilk samples from the mother on two separate occasions (once during the initiation phase and another during the continuation phase of tuberculosis treatment). The initial study design, including sampling times, was informed by a stochastic simulation and estimation exercise, with very limited prior breastmilk data. An interim analysis after recruiting 6 mother-infant pairs ascertained that our initial assumptions were ideal for achieving our study objectives and no amendments to the sampling times were necessary. Initial data from 6 mother-infant pairs show that rifampicin penetrates breastmilk with an approximate milk-to-plasma ratio of 0.169 and 0.189 on two separate visits. However, it was undetectable in most infants.

FIGURE 1

Maternal rifampicin concentration–time profiles from the first 6 participants recruited. Individual maternal rifampicin plasma and breastmilk concentration–time profiles for the first 6 participants recruited and receiving first‐line treatment for drug‐sensitive tuberculosis. Plot labels 1–6: Individual patients; Solid lines, plasma concentration–time profiles (Orange: Visit 1 [intensive phase] and green: Visit 2 [continuation phase]); dashed lines, breastmilk concentration–time profiles (orange: Visit 1 and green: Visit 2); horizontal lines, lower limit of quantification, LLOQ (purple: Plasma and black: Breast milk). Data points below the LLOQ are plotted as LLOQ/2.

FIGURE 2

Proposed population pharmacokinetic model to describe observed rifampicin plasma and breastmilk concentrations.