Lipophilic nalmefene prodrugs to achieve a one-month sustained release

Nalmefene is an opioid antagonist which as a once-a-day tablet formulation has recently been approved for reducing ethanol intake in alcoholic subjects. In order to address the compliance issue in this patient population, a number of potential nalmefene prodrugs were synthesized with the aim of providing a formulation that could provide plasma drug concentrations in the region of 0.5–1.0 ng/mL for a one-month period when dosed intramuscular to dogs or minipigs. In an initial series of studies, three different lipophilic nalmefene derivatives were evaluated: the palmitate (C16), the octadecyl glutarate diester (C18-C5) and the decyl carbamate (CB10). They were administered intramuscularly to dogs in a sesame oil solution at a dose of 1 mg-eq. nalmefene/kg. The decyl carbamate was released relatively quickly from the oil depot and its carbamate bond was too stable to be used as a prodrug. The other two derivatives delivered a fairly constant level of 0.2–0.3 ng nalmefene/mL plasma for one month and since there was no significant difference between these two, the less complex palmitate monoester was chosen to demonstrate that dog plasma nalmefene concentrations were dose-dependent at 1, 5 and 20 mg-eq. nalmefene/kg. In a second set of experiments, the effect of the chain length of the fatty acid monoester promoieties was examined. The increasingly lipophilic octanoate (C8), decanoate (C10) and dodecanoate (C12) derivatives were evaluated in dogs and in minipigs, at a dose of 5 mg-eq. nalmefene/kg and plasma nalmefene concentrations were measured over a four-week period. The pharmacokinetic profiles were very similar in both species with Cmax decreasing and Tmax increasing with increasing fatty acid chain length and the target plasma concentrations (0.5–1.0 ng/mL over a month-long period) were achieved with the dodecanoate (C12) prodrug. These data therefore demonstrate that sustained plasma nalmefene concentrations can be achieved in both dog and minipig using nalmefene prodrugs and that the pharmacokinetic profile of nalmefene can be tuned by varying the length of the alkyl group

Pharmacokinetics-Pharmacodynamics of a Respiratory Syncytial Virus Fusion Inhibitor in the Cotton Rat Model▿

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants, young children, elderly persons, and severely immunocompromised patients. Effective postinfection treatments are not widely available, and currently there is no approved vaccine. TMC353121 is a potent RSV fusion inhibitor in vitro, and its ability to reduce viral loads in vivo was demonstrated in cotton rats following prophylactic intravenous administration. Here, the pharmacokinetics of TMC353121 in the cotton rat, which is semipermissive for RSV replication, were further explored to build a pharmacokinetic-pharmacodynamic (PK-PD) model and to estimate the plasma drug levels needed for significant antiviral efficacy. TMC353121 reduced the viral titers in bronchoalveolar lavage fluid in a dose-dependent manner after a single subcutaneous administration and intranasal RSV inoculation 24 h after compound administration. The viral titer reduction and plasma TMC353121 concentration at the time of RSV inoculation were well described using a simple Emax model with a maximal viral titer reduction (Emax) of 1.5 log10. The plasma drug level required to achieve 50% of the Emax (200 ng/ml) was much higher than the 50% inhibitory concentration observed in vitro in HeLaM cells (0.07 ng/ml). In conclusion, this simple PK-PD approach may be useful in predicting efficacious exposure levels for future RSV inhibitors

Comparison of five in vitro digestion models to in vivo experimental results : lead bioaccessibility in the human gastrointestinal tract

This paper presents a multi-laboratory comparison study of in vitro models assessing bioaccessibility of soil-bound lead in the human gastrointestinal tract under simulated fasted and fed conditions. Oral bioavailability data from a previous human in vivo study on the same soil served as a reference point. In general, the bioaccessible lead fraction was significantly (P < 0.05) different between the in vitro methods and ranged for the fasted models from 2% to 33% and for the fed models from 7% to 29%. The in vivo bioavailability data from literature were 26.2 ± 8.1% for fasted conditions, compared to 2.5 ± 1.7% for fed conditions. Under fed conditions, all models returned higher bioaccessibility values than the in vivo bioavailability; whereas three models returned a lower bioaccessibility than bioavailability under fasted conditions. These differences are often due to the method's digestion parameters that need further optimization. An important outcome of this study was the determination that the method for separating the bioaccessible lead from the non-bioaccessible fraction (centrifugation, filtration, ultrafiltration) is crucial for the interpretation of the results. Bioaccessibility values from models that use more stringent separation methods better approximate in vivo bioavailability results, yet at the expense of the level of conservancy. We conclude from this study that more optimization of in vitro digestion models is needed for use in risk assessment. Moreover, attention should be paid to the laboratory separation method since it largely influences what fraction of the contaminant is considered bioaccessible

Pediatric pharmacokinetics and dose predictions: a report of a satellite meeting to the 10th Juvenile Toxicity Symposium

On the 24th of April 2019 a symposium on Pediatric pharmacokinetics and dose predictions was held as a satellite meeting to the 10th Juvenile Toxicity Symposium. The aim of this meeting was to bring together scientists from academia, industry and clinical research organizations to update each other on the current knowledge on pediatric drug development. The increased knowledge on specific ontogeny profiles of drug metabolism and transporter proteins, integrated into physiologically based pharmacokinetic (PBPK) models has allowed a more integrated understanding of age-related differences in PK, for which examples were given during the meeting. PBPK may be considered the gold-standard for pediatric PK prediction, but still it is important to know that simpler methods like allometry, allometry combined with maturation function, functions based on the elimination pathway or linear models also perform well depending on the age range or the mechanisms involved. It is important to combine knowledge from different methods and information sources; e.g. techniques like microdosing can gain early read-out of age-related differences in exposure and in addition such results can be value to verify models. To further establish best practices for dose setting in pediatrics more in vitro and in vivo research is needed on such aspects as age related changes in the exposure response relationship and also the impact of disease on PK. New information coupled with the refining of model based drug development approaches will allow faster targeting of intended age groups and allow more efficient design of pediatric clinical trials