Comparative pharmacokinetics of porcine and human anti-influenza hemagglutinin monoclonal antibodies in outbred pigs and minipigs.

Assessing the pharmacokinetics of monoclonal antibodies (mAbs) in relevant animal models is essential for designing improved formulations and developing mAb delivery platforms. We have established the pig, a large natural host animal for influenza with many similarities to humans, as a robust model for testing the therapeutic efficacy of anti-influenza mAbs and evaluating mAb delivery platforms. Here, we compared the pharmacokinetic characteristics of two anti-influenza hemagglutinin mAbs, human 2-12C and porcine pb27, in Göttingen minipigs and Landrace × Large White outbred pigs.

Respiratory benefit in preterm lambs is progressively lost when the concentration of fetal plasma betamethasone is titrated below two nanograms per milliliter.

Antenatal steroid therapy is the standard of care for women at imminent risk of preterm delivery. Current dosing regimens use suprapharmacological doses to achieve extended fetal steroid exposures. We aimed to determine the lowest fetal plasma betamethasone concentration sufficient to achieve functional preterm lung maturation.

Minimal physiologically-based hybrid model of pharmacokinetics in pregnant women: Application to antenatal corticosteroids.

Minimal physiologically-based pharmacokinetic (mPBPK) models are an alternative to full physiologically-based pharmacokinetic (PBPK) models as they offer reduced complexity while maintaining the physiological interpretation of key model components. Full PBPK models have been developed for pregnancy, but a mPBPK model eases the ability to perform a "top-down" meta-analysis melding all available pharmacokinetic (PK) data in the mother and fetus. Our hybrid mPBPK model consists of mPBPK models for the mother and fetus with connection by the placenta.

Antenatal corticosteroids in Singapore: a clinical and scientific assessment.

Preterm birth (PTB; delivery prior to 37 weeks' gestation) is the leading cause of early childhood death in Singapore today. Approximately 9% of Singaporean babies are born preterm; the PTB rate is likely to increase given the increased use of assisted reproduction technologies, changes in the incidence of gestational diabetes/high body mass index and the ageing maternal population. Antenatal administration of dexamethasone phosphate is a key component of the obstetric management of Singaporean women who are at risk of imminent preterm labour.

Pharmacokinetics of levonorgestrel and etonogestrel in rat or minipig following intravenous, subcutaneous, or intradermal administration.

The objective of these studies was to determine the pharmacokinetics of levonorgestrel and etonogestrel in Sprague-Dawley rat or Göttingen minipig following various administration routes.Four sequential crossover studies were conducted: Study 1 administered levonorgestrel 30 µg intravenously and intradermally in four minipigs; Study 2 administered levonorgestrel 30 µg intravenously in 12 rats; Study 3 administered levonorgestrel 60 µg intravenously and subcutaneously in 12 rats; and Study 4 administered etonogestrel 30 µg intravenously in 12 rats. Samples were quantified using liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were estimated via noncompartmental analysis.

Low-dose antenatal betamethasone treatment achieves preterm lung maturation equivalent to that of the World Health Organization dexamethasone regimen but with reduced endocrine disruption in a sheep model of pregnancy.

Background: The intramuscular administration of antenatal steroids to women at risk of preterm delivery achieves high maternal and fetal plasma steroid concentrations, which are associated with adverse effects and may reduce treatment efficacy. We have demonstrated that antenatal steroid efficacy is independent of peak maternofetal steroid levels once exposure is maintained above a low threshold.

Objective: This study aimed to test, using a sheep model of pregnancy, whether the low-dose antenatal steroid regimen proposed as part of the Antenatal Corticosteroids for Improving Outcomes in Preterm Newborns trial would achieve preterm lung maturation equivalent to that of the existing World Health Organization dexamethasone treatment regimen, but with reduced risk of adverse outcomes.

One percent of the clinical dose used for antenatal steroid therapy is sufficient to induce lung maturation when administered directly to the preterm ovine fetus.

Antenatal steroids (ANSs) are routinely administered to women judged to be at imminent risk of preterm delivery. Their principal benefit is precocious functional maturation of the preterm fetal lung. Current dosing regimens expose the mother and fetus to high steroid levels that may be unnecessary, increasing the potential risks of disruption to the maternal and fetal hypothalamic-pituitary-adrenal (HPA) axis and glucose regulation, alterations in placental function, and reduced fetal growth.

Continuous but not pulsed low-dose fetal betamethasone exposures extend the durability of antenatal steroid therapy.

Antenatal steroid (ANS) therapy is the standard care for women at imminent risk of preterm labor. Despite extensive and long-standing use, 40%-50% of babies exposed antenatally to steroids do not derive benefit; remaining undelivered 7 days or more after ANS treatment is associated with a lack of treatment benefit and increased risk of harm. We used a pregnant sheep model to evaluate the impact of continuous versus pulsed ANS treatments on fetal lung maturation at an extended, 8-day treatment to delivery interval.

Application of exposure bracketing to streamline the development of contraceptive products.

Developing new long-acting products of well-characterized contraceptive drugs is one way to address some of the reasons for unmet need for modern methods of family planning among women in low- and middle-income countries. Development and approval of such products traditionally follow a conventional paradigm that includes large Phase 3 clinical trials to evaluate efficacy (pregnancy prevention) and safety of the investigational product. Exposure-bracketing is a concept that applies known pharmacokinetics and pharmacodynamics of a drug substance to inform its safe and efficacious use in humans.

Estimating fetal exposure to the P-gp substrates, corticosteroids, by PBPK modeling to inform prevention of neonatal respiratory distress syndrome.

We have previously developed a maternal-fetal physiologically-based pharmacokinetic (m-f PBPK) model to dynamically predict (and verify) fetal-maternal exposure to drugs that passively diffuse across the placenta. Here, we extended the application of this model to dynamically predict fetal exposure to drugs which are effluxed by placental P-glycoprotein, namely the antenatal corticosteroids (ACS; dexamethasone [DEX], and betamethasone [BET]). To do so, we estimated both the placental P-gp mediated efflux clearance (CL) and the passive diffusion CL of the ACS.

Population pharmacodynamic modeling of intramuscular and oral dexamethasone and betamethasone effects on six biomarkers with circadian complexities in Indian women.

Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs.

Tenofovir Alafenamide for HIV Prevention: Review of the Proceedings from the Gates Foundation Long-Acting TAF Product Development Meeting.

The ability to successfully develop a safe and effective vaccine for the prevention of HIV infection has proven challenging. Consequently, alternative approaches to HIV infection prevention have been pursued, and there have been a number of successes with differing levels of efficacy. At present, only two oral preexposure prophylaxis (PrEP) products are available, Truvada and Descovy.

Population pharmacokinetic modeling of intramuscular and oral dexamethasone and betamethasone in Indian women.

Population analysis of pharmacokinetic data for five differing dosage forms and routes for dexamethasone and betamethasone in 48 healthy nonpregnant Indian women was performed that accounted for a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM). Plasma concentrations collected for two periods over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs.

Antenatal corticosteroids: a reappraisal of the drug formulation and dose.

We review the history of antenatal corticosteroid therapy (ACS) and present recent experimental data to demonstrate that this, one of the pillars of perinatal care, has been inadequately evaluated to minimize fetal exposure to these powerful medications. There have been concerns since 1972 that fetal exposures to ACS convey risk. However, this developmental modulator, with its multiple widespread biologic effects, has not been evaluated for drug choice, dose, or duration of treatment, despite over 30 randomized trials.

Pharmacokinetics and Pharmacodynamics of Intramuscular and Oral Betamethasone and Dexamethasone in Reproductive Age Women in India.

High-dose betamethasone and dexamethasone are standard of care treatments for women at risk of preterm delivery to improve neonatal respiratory and mortality outcomes. The dose in current use has never been evaluated to minimize exposures while assuring efficacy. We report the pharmacokinetics and pharmacodynamics (PDs) of oral and intramuscular treatments with single 6 mg doses of dexamethasone phosphate, betamethasone phosphate, or a 1:1 mixture of betamethasone phosphate and betamethasone acetate in reproductive age South Asian women.

Oral dosing for antenatal corticosteroids in the Rhesus macaque.

Antenatal corticosteroids (ACS) are standard of care for women at risk of preterm delivery, although choice of drug, dose or route have not been systematically evaluated. Further, ACS are infrequently used in low resource environments where most of the mortality from prematurity occurs. We report proof of principle experiments to test betamethasone-phosphate (Beta-P) or dexamethasone-phosphate (Dex-P) given orally in comparison to the clinical treatment with the intramuscular combination drug beta-phosphate plus beta-acetate in a Rhesus Macaque model.

Evaluation of Maternal Drug Exposure Following the Administration of Antenatal Corticosteroids During Late Pregnancy Using Physiologically-Based Pharmacokinetic Modeling.

Betamethasone and dexamethasone are the most widely studied antenatal corticosteroids (ACS) administered to pregnant women, just prior to the birth of a preterm neonate, to accelerate fetal lung maturation. Although betamethasone, predominantly used in developed countries, has been shown to be an effective and safe intervention for reducing neonatal mortality, the choice of ACS and optimal dosing in low and middle income countries (LMICs) remains unclear. This is primarily because the exposure-response relationships have not been established for ACS despite the long history of use.

Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus.

Objective: 8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (ETC-1002) is a small molecule with a unique mechanism of action shown in nonclinical studies to modulate pathways of cholesterol, fatty acid, and carbohydrate metabolism. In previous phase 2 clinical trials, once daily oral treatment with ETC-1002 significantly reduced low-density lipoprotein-cholesterol in patients with hypercholesterolemia. In this trial, the lipid-lowering efficacy of ETC-1002 was evaluated in patients with type 2 diabetes mellitus and hypercholesterolemia.

Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: a bench-to-bedside case study on tissue selective drug distribution.

The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.

Model-based development of gemcabene, a new lipid-altering agent.

The purpose of this study was to evaluate the value of model-based, quantitative decision making during the development of gemcabene, a novel lipid-altering agent. The decisions were driven by a model of the likely clinical profile of gemcabene in comparison with its competitors, such as 3-hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), the cholesterol absorption inhibitor ezetimibe, and their combination. Dose-response models were developed for the lipid effects (low-density lipoprotein cholesterol [LDL-C] and high-density lipoprotein cholesterol); adverse effects, such as persistent alanine aminotransferase elevation and myalgia; tolerability issues, such as headache; and risk reduction for coronary artery disease-related events for 5 statins, ezetimibe, gemcabene, and their combinations.

Udp-glucuronosyltransferase 2b7 is the major enzyme responsible for gemcabene glucuronidation in human liver microsomes.

The predominant metabolic pathway of gemcabene in humans is glucuronidation. The principal human UDP-glucuronosyltransferases (UGTs) involved in the glucuronidation of gemcabene were determined in this study. Glucuronidation of gemcabene was catalyzed by recombinant UGT1A3, recombinant UGT2B7, and recombinant UGT2B17, as well as by human liver microsomes (HLM).

Effects of avasimibe on cytochrome P450 2C9 expression in vitro and in vivo.

Avasimibe, an acyl-CoA:cholesterol acyltransferase inhibitor, has been previously shown to be a potent inducer of CYP3A4 and multiple drug resistance protein 1. We have further characterized the drug interaction potential of avasimibe by studying the inductive and inhibitory effect of this compound on major drug-metabolizing enzymes. Enzymes known to be involved in the metabolism of drugs likely to be coadministered with avasimibe, such as CYP1A1/2, CYP2C, and CYP2B6, were evaluated further by microarray analysis, Western immunoblotting, and activity assays, using rifampicin and beta-naphthoflavone as positive controls.

Avasimibe induces CYP3A4 and multiple drug resistance protein 1 gene expression through activation of the pregnane X receptor.

In vitro and clinical studies were conducted to characterize the potential of avasimibe, an acyl-CoA/cholesterol acyltransferase inhibitor to cause drug-drug interactions. Clinically, 3- and 6-fold increases in midazolam (CYP3A4 substrate) oral clearance were observed after 50 and 750 mg of avasimibe daily for 7 days, respectively. A 40% decrease in digoxin (P-glycoprotein substrate) area under the curve was observed with 750 mg of avasimibe daily for 10 days.

The Pharmacokinetics and Pharmacodynamics of Methylprednisolone in Chronic Renal Failure.

Methylprednisolone (MP) pharmacokinetics and its directly suppressive effects on cortisol secretion, circulating T-cells, and basophils in blood were compared in six chronic renal failure (CRF) subjects and six healthy controls after an IV administration of MP 0.6 mg kg(minus sign1) as the sodium succinate ester. The CRF subjects were studied between hemodialysis treatments.