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The use of indomethacin to delay delivery in preterm labor (PTL) is widely accepted; however, the optimal dosage of indomethacin in pregnancy is unknown. Here, we perform population pharmacokinetic (PK) and pharmacodynamic (PD) analyses, characterize the plasma disposition of indomethacin in pregnant women with PTL, and relate indomethacin exposure to delayed delivery and maternal/neonatal safety. We analyzed plasma and urine samples collected from a multicenter, prospective, opportunistic PK/PD study of indomethacin in pregnant women 12‐32 weeks gestation admitted with PTL. Ninety‐four participants with 639 plasma concentrations for indomethacin were included in the analysis. The final population PK (popPK) model for indomethacin was a 2‐compartment structural model with first‐order absorption and elimination and a covariate effect of body mass index on apparent oral clearance. We observed a 21%‐60% increase in apparent oral clearance observed during pregnancy. There was no clear association between indomethacin exposure and maternal or neonatal safety outcomes, or with the magnitude of delayed delivery; however, 96.7% of women treated with indomethacin had a delivery that was delayed at least 48 hours. Given the changes to indomethacin apparent oral clearance during pregnancy, and the lack of relationship between indomethacin exposure and safety, dose‐finding studies of indomethacin in pregnant women with PTL may help clarify the most safe and efficacious dosage and duration of indomethacin. [ABSTRACT FROM AUTHOR]

Osthol, a pharmacologically active ingredient in various traditional Chinese medicines, is predominantly metabolized by CYP2C9. It may be co-administered with other drugs which are metabolized by CYP2C9 in clinical medicine. However, CYP2C9*1/*2/*3 genotype on the pharmacokinetics of osthole and its metabolic diversity between rat and human are unclear. In this study, we investigated the effects of osthole on enzyme activity of CYP2C11/CYP2C9 in rat liver microsomes (RLMs) and human liver microsomes (HLMs), to distinguish metabolic manner of osthole in different species. Interestingly, we found that osthole inhibits the activity of CYP2C11 in a non-competitive manner in RLMs, while inhibits CYP2C9 activity in a competitive manner in pooled HLMs. Then, the effects of CYP2C9*1/*2/*3 allele on the pharmacokinetics of osthole were identified. In human CYP2C9 isoform, the Ki value of 21.93 μM (CYP2C9*1), 18.10 μM (CYP2C9*2), 13.12 μM (CYP2C9*3) indicate that there are individual differences in the inhibition of osthole on CYP2C9 activity. We investigated how the indomethacin pharmacokinetics was affected by osthole in SD rat. To estimate the area under the curve (AUC), maximum plasma concentration (Cmax) and apparent clearance (CL/F), indomethacin (10 mg/kg) was given orally combined with osthole (20 mg/kg) in adult SD rat. We found the value of PK on indomethacin, such as the AUC0–∞, was from 176.40 ± 17.29 to 173.74 ± 27.69 μg/ml h–1, Cmax from 9.02 ± 1.24 to 9.89 ± 0.82 μg/ml and CL/F from 0.11 ± 0.01 to 0.12 ± 0.04 mg/kg/h which were unsignificantly changed compared with the control groups. However, the Tmax was prolonged from 2.00 ± 0.00 h to 7.33 ± 1.15 h, and T1/2 increased from 8.38 ± 2.30 h to 11.37 ± 2.11 h. These results indicate that osthole could potentially affect the metabolism of indomethacin in vivo. [ABSTRACT FROM AUTHOR]

The vertebrate gut microbiota have been implicated in the metabolism of xenobiotic compounds, motivating studies of microbe-driven metabolism of clinically important drugs. Here, we studied interactions between the microbiota and indomethacin, a nonsteroidal anti- inflammatory drug (NSAID) that inhibits cyclooxygenases (COX) -1 and -2. Indomethacin was tested in both acute and chronic exposure models in mice at clinically relevant doses, which suppressed production of COX-1- and COX-2-derived prostaglandins and caused small intestinal (SI) damage. Deep sequencing analysis showed that indomethacin exposure was associated with alterations in the structure of the intestinal microbiota in both dosing models. Perturbation of the intestinal microbiome by antibiotic treatment altered indomethacin pharmacokinetics and pharmacodynamics, which is probably the result of reduced bacterial β-glucuronidase activity. Humans show considerable inter-individual differences in their microbiota and their responses to indomethacin — thus, the drug-microbe interactions described here provide candidate mediators of individualized drug responses. [ABSTRACT FROM AUTHOR]

Findings of a recent clinical study showed indomethacin has lower plasma levels and higher steady-state apparent clearance in pregnant subjects when compared to those in non-pregnant subjects reported in separate studies. Thus, in the current work we developed a pregnancy physiological based pharmacokinetic/pharmacodynamic (PBPK/PD) model for indomethacin to explain the differences in indomethacin pharmacokinetics between pregnancy and non-pregnancy. A whole-body PBPK model with key pregnancy-related physiological changes was developed to characterize indomethacin PK in pregnant women and compare these parameters to those in non-pregnant subjects. Data related to maternal physiological and biological changes were obtained from literature and incorporated into the structural PBPK model that describes non-pregnant PK data. Changes in indomethacin area under the curve (AUC), maximum concentration (Cmax) and average steady-state concentration (Cave) in pregnant women were predicted. Model-simulated PK profiles were in agreement with observed data. The predicted mean ratio (non-pregnant:second trimester (T2)) of indomethacin Cave was 1.6 compared to the observed value of 1.59. In addition, the predicted steady-state apparent clearance (CL/Fss) ratio was almost similar to the observed value (0.46 vs. 0.42). Sensitivity analysis suggested changes in CYP2C9 activity, and to a lesser extent UGT2B7, as the primary factor contributing to differences in indomethacin disposition between pregnancy and non-pregnancy. The developed PBPK model which integrates prior physiological knowledge, in vitro and in vivo data, allowed the successful prediction of indomethacin disposition during T2. Our PBPK/PD model suggested a higher indomethacin dosing requirement during pregnancy. [ABSTRACT FROM AUTHOR]

The issue of prescription of analgesics during lactation is clinically important but also complex. Most of the information available is based on single dose or short term studies, and for many drugs only a single or a few case reports have been published. As great methodological problems exist in the assessment of possible adverse drug reactions in neonates and infants, there is limited knowledge about the practical impact of the, often very low, concentrations found. Nevertheless, some recommendations can be made. Breast-feeding during maternal treatment with paracetamol (acetaminophen) should be regarded as being safe. Short term use of nonsteroidal anti-inflammatory drugs seems to be compatible with breast-feeding. For long term treatment, short-acting agents without active metabolites, such as ibuprofen, should possibly be preferred. The use of aspirin (acetylsalicylic acid) in single doses should not pose any significant risks to the suckling infant. Use of codeine is probably compatible with breast-feeding, although the effects of long term exposure have not been fully elucidated. For propoxyphene, it seems unlikely that the suckling infant will ingest amounts that will cause any detrimental effects during short term treatment. However, it cannot be excluded that significant amounts of the metabolite norpropoxyphene may arise in the suckling infant during long term exposure. Treatment of the mother with single doses of morphine or pethidine (meperidine) is not expected to cause any risk for the suckling infant. Repeated administration of pethidine, in contrast to morphine, affects the suckling infant negatively. Thus, morphine should be preferred in lactating mothers. However, during long term treatment with morphine, the importance of uninterrupted breast-feeding should be assessed on an individual basis against the potential risk of adverse drug effects in the infant. If it is decided to continue breast-feeding the infant should be observed for possible adverse effects. In general, if treatment of a lactating mother with an analgesic drug is considered necessary, the lowest effective maternal dose should be given. Moreover, infant exposure can be further reduced if breast-feeding is avoided at times of peak drug concentration in milk. As breast milk has considerable nutritional, immunological and other advantages over formula milk, the possible risks to the infant should always, and on an individual basis, be carefully weighed against the benefits of continuing breast-feeding. [ABSTRACT FROM AUTHOR]