The results confirm that the transfer of ibuprofen into breast milk decreases with the protein concentration and the duration of lactation. These results suggest that the use of ibuprofen is compatible with prolonged breastfeeding after the early postpartum stage.
Based on the efficacy/safety correlations, a therapeutic window has been defined ranging from 4.5 to 6.5 mg/L and 1.5 and 2.0 mg/L for trough Ct and Cu, respectively. For the first time, the relevance of new pharmacokinetic parameters, such as Cu and fu, has been explored and discussed, and our results support the current TDM protocol for VOR.
To date, therapeutic drug monitoring (TDM) is carried out with antiretrovirals and is usually based on total concentrations (C ). However, for some patients, TDM does not reflect efficacy or the avoidance of toxicity as is the case for atazanavir (ATV), a HIV protease inhibitor. As the unbound concentration (C ) is the pharmacological active form, the aim of the study was to evaluate the value of C and the unbound fraction (f , f = C /C ) for the TDM of ATV. The variability of C and the corresponding f of ATV was explored in 43 patients treated with ATV for an average of 13.5 months. C was determined by coupling ultrafiltration and liquid chromatography. As ATV is highly bound to alpha-1 acid glycoprotein (AAG), the correlation between f and AAG was also evaluated. The viral load was monitored to evaluate the patients' virologic response, while total plasma bilirubin and unconjugated plasma bilirubin were used as biomarkers of ATV toxicity. Median trough C and C were 37.9 μg/L (Interquartile range (IQR) 20.6-94.9 μg/L) and 628.6 μg/L (IQR 362.7-1078.1 μg/L), respectively. f , C and C showed high variability, but the f variability was not correlated with the AAG level. The unbound concentration and fraction were unrelated to the virologic response (P = 0.21 and P = 0.65 for C and f , respectively) nor to the unconjugated bilirubin (Pearson correlation coefficient (ρ), ρ = 0.22; P = 0.17 for C ). Neither total nor unbound concentrations of ATV fully explained hyperbilirubinaemia or virologic failure. From this study, we conclude that unbound ATV did not appear to be more relevant than C .
Ibuprofen is a commonly used analgesic and second therapeutic class prescribed at different stages of lactation (1). We previously published a study about 20 women who received a mean daily dose of 1.012 mg (AE96 mg) of ibuprofen to treat pain or inflammatory disorders (2). Ibuprofen milk concentrations were measured using high-performance liquid chromatography, and the mean concentration was 360 AE 160 lg/L. The mean ibuprofen transfer infant dose was 68 (8-262) lg/kg/day and the relative infant dose was <0.38% (0.04-1.53) of the weight-adjusted maternal daily dose, which was equal to 0.2% of the paediatric dose. Our advice is that ibuprofen is safe in the post-partum and later post-partum periods because the relative infant dose is very low in colostrum or mature milk. When Townsend et al. studied ibuprofen transfer in colostrum and Rigourd et al. studied it in mature milk, the relative infant dose was always under 1% (2,3). Our current belief is that there are sufficient pharmacokinetic data to confirm that there is a very poor transfer of ibuprofen from the mother's milk to the neonate. We have concluded that the use of ibuprofen is compatible with breastfeeding after the early post-partum stage and with prolonged breastfeeding (2).Codeine, like ibuprofen, is often used as antalgic during the post-partum period. However, recent data have shown that codeine could trigger serious adverse events, even neonatal death (3,4), during breastfeeding. In contrast, ibuprofen did not show any adverse events. Codeine is fully metabolised by cytochrome 2D6, while ibuprofen is partially metabolised by CY2C8 (5) and preferentially metabolised by CYP2C9 (6).We studied the cytochrome P450 enzymes involved in ibuprofen metabolism: CYP2C8 and CYP2C9. DNA was extracted from 13 frozen breastmilk samples in 1-mL aliquots, using the Qiagen Kit (QiaSymphony DSP DNA; Qiagen, Courtaboeuf France). All the DNA was amplified by screening with taqman technology for cytochrome P450 polymorphism. Genotype analysis was carried out for cytochromes CYP 2C8 and CYP2C9. All laboratory procedures were performed in accordance with the local ethics committee (CPP Ile de France) and pharmacogenetics standard operating laboratory procedures at Paris South University's School of Medicine. The chi-square test was used to compare the genotype frequencies and the associations with CYP2C8 and CYP2C9.We obtained a sufficient concentration of good-quality DNA (Table 1). Allelic variants were present in the same proportion as in the Caucasian population. For every genetic polymorphism, the relative infant dose of ibuprofen was less than 1.56%.These polymorphisms determine the pharmacokinetics of ibuprofen. Interindividual variability in drug metabolism is a major cause of adverse drug effects, and in nonsteroidal anti-inflammatory drugs (NSAIDs), this variability is linked to polymorphisms in genes coding for drug-metabolising enzymes. Both CYP2C8 and CYP2C9 contribute equally to the metabolism of ibuprofen (7). The main CYP2C9 polymorphisms responsible for t...
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