Effects of Rifampicin On Pyrotinib Maleate Pharmacokinetics In Healthy Subjects

Purpose: Pyrotinib (PTN) is primarily metabolized by cytochrome P450 (CYP)3A4 isozyme. Rifampicin (RIF) is a strong CYP3A4 inducer. Thus, the effect of oral RIF on PTN pharmacokinetics (PK) was evaluated to provide dose recommendation when co-administered.Method: This phase I, open-label study investigated the effects of steady-state RIF administration on single-dose PK of PTN, in 18 healthy participants who received PTN 400 mg single doses on days 1 and 13, and were administrated with RIF 600 mg qd on days 6-16. Each dose for RIF was administrated on an empty stomach, PTN were administrated orally in the morning 30 min after the start of the standard meal. Serial PK samples for PTN were collected on day 1 and day 13. Plasma PTN PK parameters were determined with non-compartmental analysis. Geometric least-squares mean ratios (GMRs) and 90% confidence intervals (CIs) were generated by the mixed-effected model for within-subject treatment comparisons. Safety assessments were performed throughout the study.Results: Eighteen subjects were enrolled and 15 completed the study. RIF significantly reduced PTN exposure: GMRs (90 % CI) for PTN + RIF versus PTN alone were 0.04 (0.034,0.049), 0.04 (0.037,0.054), and 0.11 (0.09,0.124) for area under the curve from time zero to time of last quantifiable concentration (AUC0-t), area under the curve from time zero to infinity (AUC0-∞ ), and maximum observed plasma concentration(Cmax), respectively. PTN alone and co-administered with RIF was well tolerated.Conclusion: Concurrent administration of PTN and RIF was associated with significantly decreased systemic exposure to PTN. The findings suggest that concomitant strong CYP3A4 inducers should be avoided during PTN treatment. Concurrent administration of PTN and RIF was well tolerated.

ESTIMACIÓN DE UNA DOSIS DE MARBOFLOXACINA PARA CABRAS DE TRES SEMANAS DE EDAD MEDIANTE ANÁLISIS POBLACIONAL

A dose of marbofloxacin (MFX) to treat gastrointestinal infections caused by E. coli in 3-week-old goats was estimated. The pharmacodynamics of MFX against E. coli was evaluated in vitro by estimation of minimum inhibitory concentration (MIC), minimum bactericide concentration (MBC) and mutant prevention concentration (MPC). Marbofloxacin was administered to six 3-week-old goats by subcutaneous route at the dose of 2 mg/kg. The pharmacokinetic parameters were estimated by non-compartmental analysis. The dose of MFX capable to protect the 95% of population was calculated considering the population distribution of pharmacokinetic parameters. The efficacy of MFX was evaluated by the relationship between the area under curve and MPC (AUC/MPC) with a cut-off value of 22 h. The results showed that the estimated dose of MFX to reach the clinical outcome of gastrointestinal infections caused by E. coli and to prevent the bacterial resistance at the 95% of the population of 3-week-old goats was 3,179 mg/kg, which for practical reasons was fixed at 3,5 mg/kg. The in vivo efficacy of dose estimated will be tested in future studies.

FARMACOCINÉTICA Y BIODISPONIBILIDAD ABSOLUTA DE MARBOFLOXACINA EN BÚFALOS (Bubalus bubalis)

The aim of this study was to evaluate the pharmacokinetic behaviour and the absolute bioavailability of marbofloxacin (MFX) in adult water buffaloes and to estimate the pharmacokinetic parameters for calculating the therapeutic dose in this animal species. Six adult buffaloes (3 males and 3 females) where treated by intravenous (IV) and subcutaneous (SC) route with a 10% experimental MFX injectable formulation at the dose of 2 mg/kg. After administration blood samples were drawn at pre-established times and MFX plasma concentrations where determined by microbiologic method. The pharmacokinetic analysis was made by compartmental analysis. After IV administration MFX presented a clearance of 198.4 ± 21.0 mL.kg.h and a half-life of elimination of 7.64 ± 3.29 h. After SC administration marbofloxacin presented a half-life of elimination of 8.5 ± 2.42 h, reaching it maximum plasma concentration (1.67 ± 0.516 μg/mL) at 1.69 ± 0.231 h, with a bioavailability of 80.8 ± 11.2 %. The estimated values of clearance and bioavailability will be employed in further studies for calculating the therapeutic dose of MFX in water buffaloes.

Effect of CYP3A4 metabolism on sex differences in the pharmacokinetics and pharmacodynamics of zolpidem

To investigate pharmacokinetic and pharmacodynamic differences of zolpidem between males and females and their causes, including CYP3A4 activity. A single oral dose of zolpidem (10 mg) was administered to 15 male and 15 female healthy subjects. Blood samples were collected up to 12 h post-dose to determine plasma zolpidem concentrations. Pharmacokinetic parameters were obtained using non-compartmental analysis. Digit symbol substitution test, choice reaction time, and visual analog scale of sleepiness were used to evaluate pharmacodynamics. We measured CYP3A4 activity using 4β-hydroxycholesterol, an endogenous metabolite. Mean maximum plasma concentration and area under the plasma concentration–time curve were higher for females than for males (9.9% and 32.5%, respectively); other pharmacokinetic parameters showed no significant differences. Pharmacodynamic scores for females showed delayed recovery compared with that for males. CYP3A4 activity was higher in females than in males (p = 0.030). There was no serious adverse event, and adverse event incidence was not different between the sexes. Zolpidem exposure was about 30% higher in females than in males. Delayed pharmacodynamic score recovery in females could be related to higher zolpidem concentrations. Although apparent clearance was lower in females, systemic clearance might not be the cause of the different exposures to zolpidem.

Long-Term Pharmacokinetics of Dalbavancin in ABSSSI and Osteoarticular Settings: A Real-Life Outpatient Context

Dalbavancin is a lipoglycopeptide approved for treatment of Gram-positive infections of skin and skin-associated structures (ABSSSI). Currently, off-label use at high dosages for osteoarticular infections deserves attention. This work aimed to study the long-term plasma pharmacokinetics of dalbavancin in outpatients with ABSSSI or osteoarticular infections, treated either with one or two 1500 mg doses of dalbavancin. A liquid chromatography-tandem mass spectrometry method was used to measure total dalbavancin concentrations in plasma samples. The results were analyzed through a non-compartmental analysis (NCA). Breakpoint minimum inhibitory concentration (MIC) was used to calculate AUC/MIC and T>MIC parameters, adjusted by 93% protein binding. A total of 14 patients were enrolled, 11 with osteoarticular infection and 3 with ABSSSI. Long-term pharmacokinetics showed median T>MIC (0.125 mg/L) of 11.9 and 13.7 weeks for single and dual dose, respectively. Similarly, median AUC0-2w/MIC ratios of 20,590 and 31,366 were observed for single and dual dose regimens, respectively. No adverse events were observed, and treatment success was achieved in 12/14 patients. Failure was associated with the worst clinical conditions, bone infections, and single dose. The results of this study show that dalbavancin exposure exceeds previously suggested pharmacodynamic targets. Optimization of these targets is needed for the osteoarticular setting.

Does the Amount of Stable Isotope Dose Influence Retinol Kinetic Responses and Predictions of Vitamin A Total Body Stores by the Retinol Isotope Dilution Method in Theoretical Children and Adults?

Background To minimize both cost and perturbations to the vitamin A system, investigators limit the amount of stable isotope administered when estimating vitamin A total body stores (TBS) by retinol isotope dilution (RID). Objectives We hypothesized that reasonable increases in the mass of stable isotope administered to theoretical subjects would have only transient impacts on vitamin A kinetics and minimal effects on RID-predicted TBS. Methods We adapted previously-used theoretical subjects (3 children, 3 adults) with low, moderate, or high assigned TBS and applied compartmental analysis to solve a steady state model for tracer and tracee using assigned values for retinol kinetic parameters and plasma retinol. To follow retinol trafficking when increasing amounts of stable isotope were administered [1.39-7 (children) and 2.8-14 µmol retinol (adults)], we added assumptions to an established compartmental model so that plasma retinol homeostasis was maintained. Using model-simulated data, we plotted retinol kinetics versus time and applied the RID equation TBS = FaS/SAp [Fa, fraction of dose in stores; S, retinol specific activity (SA) in plasma/SA in stores; SAp, SA in plasma] to calculate vitamin A stores. Results The model predicted that increasing the stable isotope dose caused transient early increases in hepatocyte total retinol; increases in plasma tracer were accompanied by decreases in tracee to maintain plasma retinol homeostasis. Despite changes in kinetic responses, RID accurately predicted assigned TBS (98-105%) at all loads for all theoretical subjects from 1-28 d postdosing. Conclusions Results indicate that, compared with doses of 1.4–3.5 µmol used in recent RID field studies, doubling the stable isotope dose should not affect accuracy of TBS predictions, thus allowing for experiments of longer duration when including a super-subject design (Ford et al., J Nutr 2020;150:411–8) and/or studying retinol kinetics.

Pharmacokinetics and bioequivalence of generic etoricoxib in healthy volunteers

Introduction/Study Objectives: A bioequivalence study was performed to compare the pharmacological profile of innovator etoricoxib (ETO) with a newly developed generic ETO, both in a 120 mg tablet formulation. A dissolution study was conducted to optimize the formulation process before evaluating physical changes in the active pharmaceutical ingredient and the formulated product. Methods: This was a randomized, open-label, balanced, two-treatment, two-period, two-sequence, single-dose, two-way crossover, truncated bioequivalence study involving a washout period of ten days. A total of 26 healthy male volunteers were recruited. The pharmacokinetic profile of the test formulation was compared with the reference formulation. Results/Discussion: The pharmacokinetic parameters of ETO were calculated based on the plasma drug concentration-time profile using non-compartmental analysis to determine its safety profile and tolerability. The Test/Reference (T/R) ratio of ETO was 104.36% (90% confidence interval (CI): 98.30%–110.80%) for area under curve (AUC)0-72 while the T/R ratio of maximum concentration (Cmax) was 101.39% (92.15%–111.56%). The 90% CI of the Cmax and AUC0-72 of ETO were within acceptable bioequivalence limits of 80%–125%. All values were within the predetermined limits of the Association of Southeast Asian Nation (ASEAN) bioequivalence guidelines. Conclusion: The test formulation was found to be bioequivalent with respect to the reference drug, according to ASEAN bioequivalence guidelines.

Pharmacokinetic-Pharmacodynamic Profile, Bioavailability, and Withdrawal Time of Tylosin Tartrate Following a Single Intramuscular Administration in Olive Flounder (Paralichthys olivaceus)

The objective of this study was to demonstrate the pharmacokinetic–pharmacodynamic profile, bioavailability, and withdrawal time of tylosin tartrate (TT) administered to olive flounder via intramuscular (IM, 10 or 20 mg/kg, n = 240) and intravascular (IV, 10 mg/kg, n = 90) injections. Serum concentrations of tylosin were determined using a validated liquid chromatography-tandem mass spectrometry method. According to the non-compartmental analysis, the bioavailability of TT was 87%. After the IV injection, the terminal half-life, total body clearance, volume of distribution, and mean residence time of TT were 21.07 h, 0.07 L/kg/h, 2.15 L/kg, and 16.39 h, respectively. Rapid absorption (Tmax 0.25 h), prolonged action (terminal half-life, 33.96 and 26.04 h; MRT, 43.66 and 33.09 h), and linear dose–response relationship (AUC0-inf, 123.55 and 246.05 µg/mL*h) were monitored following 10 and 20 mg/kg IM injection. The withdrawal time of TT from muscle (water temperature, 22 °C) was 9.84 days, rounded up to 10 days (220 degree days). Large Cmax/MIC90, AUC0-inf/MIC90, and T > MIC90 values were obtained for Streptococcus isolates and these PK/PD indices satisfied the criteria required for efficacy evaluation. This study lays a foundation for the optimal use of TT and provides valuable information for establishing therapeutic regimens.

Pregnancy and Lactation Alter Vitamin A Metabolism and Kinetics in Rats under Vitamin A-Adequate Dietary Conditions

Background: Vitamin A (VA) plays critical roles in prenatal and postnatal development; however, limited information is available regarding maternal VA metabolism during pregnancy and lactation. Objectives: We investigated the impact of pregnancy and lactation on VA metabolism and kinetics in rats, hypothesizing that changes in physiological status would naturally perturb whole-body VA kinetics. Methods: Eight-week old female rats (n = 10) fed an AIN-93G diet received an oral tracer dose of 3H-labeled retinol to initiate the kinetic study. On d 21 after dosing, six female rats were mated. Serial blood samples were collected from each female rat at selected times after dose administration until d 14 of lactation. Model-based compartmental analysis was applied to the plasma tracer data to develop VA kinetic models. Results: Our compartmental model revealed that pregnancy resulted in a gradual increase in hepatic VA mobilization, presumably to support different stages of fetal development. Additionally, the model indicates that during lactation, VA derived from dietary intake was the primary source of VA delivered to the mammary gland for milk VA secretion. Conclusion: During pregnancy and lactation in rats with an adequate VA intake and previous VA storage, the internal redistribution of VA and increased uptake from diet supported the maintenance of VA homeostasis.