Noncompartmental Pharmacokinetic Parameters Research Articles

Effects of multiple-dose administration of zavegepant nasal spray on the single-dose pharmacokinetics of ethinyl estradiol-levonorgestrel.

The potential for drug-drug interaction of multiple-dose intranasal zavegepant on the single-dose oral contraceptive ethinyl estradiol and levonorgestrel (EE-LNG) was evaluated. Zavegepant (as a nasal spray) is a calcitonin gene-related peptide receptor antagonist approved in the United States for treatment of acute migraine in adults. This single-center, Phase 1, open-label, fixed-sequence study included healthy, nonsmoking females (18-45 years old). In treatment Period 1, a single oral dose of EE-LNG 0.02-0.10 mg was administered on Day 1. In treatment Period 2, intranasal zavegepant (20 mg daily; 10 mg per nostril separated by 1 h) was administered on Days 1-5; 1 oral dose of EE-LNG 0.02-0.10 mg was administered immediately after first 10 mg intranasal zavegepant dose on Day 2. Blood samples for EE-LNG concentrations were collected on Day 1, treatment Period 1, and Day 2, treatment Period 2, and zavegepant concentrations on Day 2, treatment Period 2. Noncompartmental pharmacokinetic parameters included maximum observed concentration (Cmax), area under the concentration-time curve (AUC) from Time 0 to last non-zero concentration (AUC0-t), and AUC from Time 0 to infinity (AUC0-inf). The safety and pharmacokinetic sample sizes were 26 and 23, respectively. Statistical comparisons of pharmacokinetic exposure parameters after co-administration of zavegepant and EE-LNG versus EE-LNG alone showed small, but statistically insignificant, changes in either EE or LNG exposure. EE comparison ratios (90% confidence intervals [CIs]) were 109.9% (105.3%, 114.8%) for AUC0-inf and 110.2% (104.6%, 116.1%) for Cmax. LNG comparison ratios (90% CIs) were 107.0% (100.2%, 114.3%) for AUC0-inf and 108.8% (99.9%, 118.4%) for Cmax. Frequently reported treatment-emergent adverse events included dysgeusia (n = 25, 96%), throat irritation (n = 11, 42%), headache (n = 10, 39%), nasal discomfort (n = 7, 27%), pharyngeal paresthesia (n = 5, 19%), and nausea (n = 4, 15%). Co-administration of zavegepant nasal spray with a single dose of an oral contraceptive resulted in no clinically meaningful changes (<12% increase) in EE-LNG exposure.

Meta-Analysis of Noncompartmental Pharmacokinetic Parameters to Evaluate the Impact of CYP2C19 and CYP2C9 Genetic Polymorphisms on Abrocitinib Exposure.

Abrocitinib is a selective Janus kinase 1 inhibitor approved for the treatment of atopic dermatitis. It is metabolized primarily by cytochrome P450 (CYP) 2C19 (approximately 53%) and CYP2C9 (approximately 30%), which form 2 active metabolites. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of abrocitinib and those metabolites with active moiety area under the plasma concentration-time curve (AUC) considered the best measure of the total pharmacological effect. The effect of CYP2C19 and/or CYP2C9 genotypes on abrocitinib and active moiety exposures were evaluated using a meta-analysis of the noncompartmental estimates of exposure pooled from 10 clinical studies. A linear mixed-effects model was developed on the basis of the power model to evaluate the effect of CYP2C19 and/or CYP2C9 genotypes on exposure (i.e., abrocitinib AUC and peak plasma concentration, active moiety AUC and peak plasma concentration). The genotypes were evaluated individually and as a combined phenotype effect. When evaluating the poor metabolizers of CYP2C19 or CYP2C9 individually, the estimated increases were 44.9% and 42.0% in active moiety AUC, respectively. The combined phenotype models showed a 0.6% decrease, and 25.1% and 10.5% increases in the active moiety AUC for "elevated," "mixed," and "reduced" metabolizers, respectively. Overall, the active moiety exposures did not appear to be affected to a clinically meaningful extent by different genotypes of CYP2C19 and/or CYP2C9.

Pharmacokinetics and Tissue Distribution of Itampolin A following Intragastric and Intravenous Administration in Rats Using Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry.

Itampolin A, a natural brominated tyrosine alkaloid isolated from the sponge Iotrochota purpurea, has been shown to have good inhibitory effects in lung cancer cells as a p38α inhibitor. A simple, sensitive, and reliable ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method has been established, validated, and applied to the study of the pharmacokinetics and tissue distribution of itampolin A following intragastric and intravenous administration. Itampolin A and theophylline (internal standard, IS) were extracted by the simple protein precipitation technique using methanol as the precipitating solvent. Chromatographic separation was achieved by using the optimized mobile phase of a 0.1% formic acid aqueous solution and acetonitrile in the gradient elution mode. Itampolin A and IS were detected and quantified using positive electrospray ionization in the multiple reaction monitoring mode with transitions of m/z 863.9 → 569.1 for itampolin A and m/z 181.1 → 124.1 for IS, respectively. The assay exhibited a linear dynamic range of 1-1600 ng/mL for itampolin A in biological samples and the low limit of quantification was 1 ng/mL. Non-compartmental pharmacokinetic parameters indicated that itampolin A was well-absorbed into the systemic circulation and rapidly eliminated after administration. The apparent distribution volume of itampolin A was much higher after intragastric administration than that after intravenous administration. A tissue distribution study showed that itampolin A could be detected in different tissues and maintained a high concentration in the lung, which provided a material basis for its effective application in lung cancer. The pharmacokinetic process and tissue distribution characteristics of imtapolin A were expounded in this study, which can provide beneficial information for the further research and clinical application of itampolin A.

Deep-NCA: A deep learning methodology for performing noncompartmental analysis of pharmacokinetic data.

Noncompartmental analysis (NCA) is a model-independent approach for assessing pharmacokinetics (PKs). Although the existing NCA algorithms are very well-established and widely utilized, they suffer from low accuracies in the setting of sparse PK samples. In response, we developed Deep-NCA, a deep learning (DL) model to improve the prediction of key noncompartmental PK parameters. Our methodology utilizes synthetic PK data for model training and uses an innovative patient-specific normalization method for data preprocessing. Deep-NCA demonstrated adequate performance across six previously unseen simulated drugs under multiple dosing, showcasing effective generalization. Compared to traditional NCA, Deep-NCA exhibited superior performance for sparse PK data. This study advances the application of DL to PK studies and introduces an effective method for handling sparse PK data. With further validation and refinement, Deep-NCA could significantly enhance the efficiency of drug development by providing more accurate NCA estimates while requiring fewer PK samples.

Proton Pump Inhibitors Do Not Affect the Bioavailability of a Novel Liquid Formulation of Levothyroxine

ObjectiveThis study evaluates the impact of a representative proton pump inhibitor (PPI) (omeprazole), administered simultaneously or staggered, on the pharmacokinetics of levothyroxine (LT4) solution (Tirosint-SOL). MethodsThis was a randomized, 3-way crossover, comparative bioavailability study in 36 healthy adults under fasting conditions.Omeprazole 40 mg delayed-release capsule was administered once daily from Day 1 to 6 (mornings, Treatment-A; evenings, Treatment-B; none, Treatment-C) to increase and stabilize gastric pH. In the morning of Day 5, a single dose of LT4 solution 600 mcg was administered. Blood samples were collected 0 to 48 hours post-LT4 administration. Noncompartmental pharmacokinetic parameters were calculated for total serum thyroxine using baseline-corrected data. Maximum concentration (Cmax) and area under the concentration-time curve (AUC0-48) were included in an analysis of variance to obtain geometric mean ratios and 90% confidence intervals. ResultsFor both comparisons (A/C and B/C), geometric mean ratios and 90% confidence intervals for all parameters were within the equivalence boundaries (80%-125%), indicating bioequivalence: for A/C, AUC0-48 98.98% [94%-104%], and Cmax 91.68% [87%-97%]; for B/C, AUC0-48 98.94% [95%-103%], and Cmax 94.90% [90%-100%]. Median Tmax (time associated with Cmax) was similar across treatments. ConclusionThis study demonstrated that Tirosint-SOL bioavailability is unaffected by coadministration of a representative PPI, given simultaneously or staggered by about 12 hours, compared to administration of LT4 solution alone. For hypothyroid patients on PPI therapy, administration of LT4 solution may reduce variations in thyroid stimulating hormone levels related to intermittent use of acid-reducing drugs and consequently the need for dose adjustments.

Effect of Daridorexant on the Pharmacokinetics of Midazolam, and on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects.

Daridorexant, a dual orexin receptor antagonist was recently approved for the treatment of insomnia at doses up to 50 mg once per night. This study investigated the effect of single-dose and multiple-dose daridorexant 50 mg at steady state on the pharmacokinetics (PK)of the cytochrome P450 (CYP) 3A4-sensitive substrate midazolam, and the effect of single-dose daridorexant 50 mg on the PK and pharmacodynamics(PD) of the CYP2C9-sensitive substrate warfarin. In this prospective, single-center, open-label, fixed-sequence, phase I, drug-drug interaction study, 18 healthy male subjects sequentially received Treatment A, B, and C in three periods. Treatment A consisted of a single oral concomitant administration of midazolam 2 mg and warfarin 25 mg on day 1 of the first period. Treatment B consisted of one oral administration of daridorexant 50 mg followed 1 h later by a single oral dose of midazolam 2 mg concomitantly with a single oral dose of warfarin 25 mg on day 1 and a once-daily oral administration of daridorexant 50 mg for 6 days of the second period. Treatment C consisted of a single oral administration of daridorexant 50 mg at steady state followed 1 h later by a single oral administration of midazolam 2 mg on day 1 of the third period. Blood samples were assessed for midazolam and S-warfarin PK, and PD (international normalized ratio and factor VII). Noncompartmental PK parameters and PD variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment B/A versus C/A for midazolam, and treatment B/A for warfarin. Safety and tolerability of each treatment were also assessed. Midazolam maximum plasma concentration(Cmax) and area under the plasma concentration-time curve from 0 to 24 h(AUC0-24) were 1.13- and 1.42-fold higher, respectively, after single-dose administration of daridorexant 50 mg compared to administration of midazolam alone, while Cmax and AUC0-24 were 1.12- and 1.35-fold higher, respectively, after administration of daridorexant 50 mg once daily at steady state. Terminal half-life and time to maximum plasma concentration were comparable between treatments. Daridorexant had no influence on the PK and PD of warfarin. All treatments were safe and well tolerated. Daridorexant at 50 mg is classified as a weak CYP3A4 inhibitor after single- and multiple-dose administration once daily at steady state. Daridorexant 50 mg did not induce CYP3A4 activity or inhibit CYP2C9 activity. This trial (NCT05480488) was registered on 29 July, 2022.

Pharmacokinetics and Pharmacodynamics of Etripamil, an Intranasally Administered, Fast-Acting, Nondihydropyridine Calcium Channel Blocker.

Etripamil, a fast-acting nondihydropyridine L-type calcium channel blocker, is under investigation for potential self-administration for the acute treatment of supraventricular tachyarrhythmias in a medically unsupervised setting. We report detailed pharmacokinetics and pharmacodynamics of intranasally administered etripamil in healthy adults from 2 Phase 1, randomized, double-blind studies: Study MSP-2017-1096 (sequential dose-escalation, crossover study design, n = 64) and NODE-102 (single dose, 4-way crossover study, n = 24). Validated bioanalytical assays determined plasma concentrations of etripamil and its inactive metabolite. Noncompartmental pharmacokinetic parameters were calculated. Pharmacodynamic parameters were determined for PR interval, blood pressure, and heart rate. Etripamil was rapidly absorbed intranasally, with time to maximal plasma concentration of 5-8.5 minutes, corresponding to a rapid greater than 10% increase in mean maximum PR interval from baseline within 4-7 minutes of doses of 60mg or greater. Following peak plasma concentrations, systemic etripamil levels declined rapidly within the first 15 minutes following dosing and decreased more gradually thereafter. PR interval prolongation greater than 10% from baseline was generally sustained for about 45 minutes at doses of 60mg or greater. The mean terminal half-life ranged from about 1.5 hours with 60mg to about 2.5-3 hours for the 70- and 105-mg doses. Etripamil was generally well tolerated without symptomatic hypotension. Adverse events were primarily mild to moderate and related to the administration site; no serious adverse events or episodes of atrioventricular block occurred. Intranasal etripamil administration, at doses of 60mg or greater, produced rapidly occurring slowing of atrioventricular nodal conduction with a limited duration of effect without hemodynamic or electrocardiographic safety signals in healthy volunteers.

Pharmacokinetics of Long-Acting Methylphenidate: Formulation Differences, Bioequivalence, Interchangeability.

A literature search was conducted in EMBASE, Medline, and Cochrane Library with no time limits. Study characteristics, non-compartmental pharmacokinetic parameters, and bioequivalence data were extracted for analysis. Thirty-three studies were identified with primary pharmacokinetic data after the administration of ER MPH, of which 10 were direct comparative studies (i.e., at least 2 formulations tested within a single setting) and 23 were indirect comparisons (i.e., different experimental settings). Two formulations were consistently reported as bioequivalent across the regulatory bodies using criteria from their guidance documents, although inconsistencies have been observed. However, when additional kinetic criteria (discussed in this manuscript) were imposed, only one study met the more stringent definition of bioequivalence. Various clinical factors also had inconsistent effects on the pharmacokinetics and interchangeability of the different formulations, which were associated with a lack of standardization for assessing covariates across the regulatory agencies. Additional pharmacokinetic parameters and consistency in guidelines across the regulatory bodies may improve bioequivalence assessments. Based on our findings, more research is also required to understand whether bioequivalence is an appropriate measure for determining MPH interchangeability. This critical review is suitable for formulation scientists, clinical pharmacologists, and clinicians.

Pharmacokinetics of Two Nanoemulsion Formulations of Δ8-Tetrahydrocannabinol in Rats.

The use of Δ8-tetrahydrocannabinol (Δ8-THC) has increased in recent years. Given that the oral absorption of cannabinoids in oil formulations is typically slow and variable, nanoemulsions may be an improved delivery vehicle. Therefore, we characterized the pharmacokinetics (PK) in Sprague-Dawley rats following the administration of three different oral formulations containing 10 mg/kg Δ8-THC: a translucent liquid nanoemulsion, a reconstituted powder nanoemulsion, and a medium chain triglyceride (MCT) oil solution for comparison. Δ8-THC was also administered intravenously at 0.6 mg/kg. Plasma samples were quantified for Δ8-THC and two metabolites, 11-hydroxy-Δ8-THC (11-OH-Δ8-THC) and 11-carboxy-Δ8-THC (COOH-Δ8-THC). Non-compartmental PK parameters were calculated, and a PK model was developed based on pooled data. Despite a smaller median droplet size of the translucent liquid nanoemulsion (26.9 nm) compared to the reconstituted powder nanoemulsion (168 nm), the PK was similar for both. The median Tmax values of Δ8-THC for the nanoemulsions (0.667 and 1 h) were significantly shorter than the median Tmax of Δ8-THC in MCT oil (6 h). This resulted in an approximately 4-fold higher Δ8-THC exposure over the first 4 h for the nanoemulsions relative to the MCT oil solution. The active 11-OH-Δ8-THC metabolite followed a similar pattern to Δ8-THC. The non-compartmental bioavailability estimates of Δ8-THC for the nanoemulsions (11-16.5%) were lower than for the MCT oil solution (>21.5%). However, a model-based analysis indicated similar bioavailability for all three oral formulations. These results demonstrate favorable absorption properties of both nanoemulsions, despite the difference in droplet sizes, compared to an MCT oil formulation.

Effect of Daridorexant on the Pharmacokinetics of P-Glycoprotein Substrate Dabigatran Etexilate and Breast Cancer Resistance Protein Substrate Rosuvastatin in Healthy Subjects.

The dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of insomnia at doses up to 50 mg once per night. This study aimed at investigating the effect of daridorexant 50 mg at steady state on the pharmacokinetics of dabigatran, the active moiety of dabigatran etexilate, and rosuvastatin, sensitive substrates of P-glycoprotein and breast cancer resistance protein, respectively. This single-center, open-label, fixed-sequence study enrolled 24 healthy male subjects who were dosed orally with dabigatran etexilate 75 mg on days 1 (Treatment A1) and 9 (Treatment C1) as well as rosuvastatin 10 mg on days 3 (Treatment A2) and 11 (Treatment C2). On days 7-14, daridorexant (50 mg once daily) was administered. Blood samples for the pharmacokinetics of both substrates and the pharmacodynamics of dabigatran, i.e., two coagulation tests, were collected and safety assessments performed. Noncompartmental pharmacokinetic parameters and pharmacodynamic variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment C1/C2 versus A1/A2. Geometric mean ratios (90% confidence interval) of dabigatran maximum plasma concentration and area under the plasma concentration-time curve were 1.3 (1.0-1.7) and 1.4 (1.1-1.9), respectively, whereas the time to maximum plasma concentration and terminal half-life were comparable between treatments. Pharmacodynamic variables showed a similar pattern as dabigatran pharmacokinetics in both treatments. Rosuvastatin pharmacokinetics were unchanged upon concomitant daridorexant administration. All treatments were well tolerated. A mild inhibition of P-glycoprotein was observed after administration of daridorexant (50 mg once daily) at steady state, whereas breast cancer resistance protein was not affected. NCT05480475; date of registration: 29 July, 2022.

Cariprazine in Pediatric Patients with Autism Spectrum Disorder: Results of a Pharmacokinetic, Safety and Tolerability Study.

Objective: Cariprazine is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This study, which is the first to evaluate cariprazine in pediatric patients with autism spectrum disorder (ASD) (including children 5-9 years of age) using an oral solution formulation, evaluated the safety, tolerability, pharmacokinetics (PK), and exploratory efficacy of cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Methods: This clinical pharmacology, open-label, multiple-dose study enrolled 25 pediatric patients from 5 to 17 years of age, who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for ASD. All patients began treatment with cariprazine 0.5 mg once daily (QD) and underwent a titration over 7 days to maintenance doses of 1.5 or 3 mg QD for patients 13-17 years of age at Screening, 0.75 or 1.5 mg QD for patients 10-12 years of age at Screening, and 0.5 or 1.5 mg QD for patients 5-9 years of age at Screening. After 6 weeks total of dosing, there was a 6-week follow-up period. Study assessments included adverse events (AEs), safety parameters, noncompartmental PK parameters, and exploratory efficacy assessments, including the Aberrant Behavior Checklist-Irritability Subscale (ABC-I), Clinical Global Impressions (CGI-S), Caregiver Global Impressions (CgGI-S), Children's Yale-Brown Obsessive Compulsiveness Scale Modified for ASD (CYBOCS-ASD), Social Responsiveness Scale (SRS), and Vineland Adaptive Behavior Scale (VABS-III). Results: All AEs were mild or moderate in severity. Most frequent treatment-emergent adverse events (TEAEs) were increased weight, increased alanine aminotransferase, increased appetite, dizziness, agitation, and nasal congestion. Increases in weight were not considered clinically meaningful. Two subjects reported extrapyramidal symptom-related TEAEs that resolved without leading to discontinuation. Dose-normalized exposures of all analytes were modestly higher in pediatric patients from 5 to 9 years of age when compared to older patients. Consistent with previous studies, at steady state, the rank of exposure in plasma was DDCAR > cariprazine > DCAR. There was numerical improvement on all exploratory endpoints (ABC-I, CGI-S, CgGI-S, CYBOCS-ASD, SRS, and VABS-III). Conclusions: PK of cariprazine and its metabolites were characterized in pediatric patients with ASD at doses up to 3 mg QD (13-17 years) and 1.5 mg QD (5-12 years). Caripazine treatment was generally well tolerated and results from this study will inform the selection of appropriate pediatric doses for subsequent studies.

Development of UPLC-MS/MS method for the determination of colistin in plasma and kidney and its application in pharmacokinetics

Recently, the frequent emergence of multidrug-resistant gram-negative bacterial infections has forced colistin to be used as one of the last-line options for the treatment of these infections. This study aimed to establish and validate a simple, rapid, and reliable method for the quantitative determination of colistin in plasma and kidney homogenates by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters of colistin sulfate in rats and the relationship between renal accumulation and time of administration in rats were estimated by measuring plasma and renal colistin concentrations. The colistin in the sample was precipitated by acetonitrile, followed by extraction with nitrogen blow-drying and reconstitution. The chromatographic separation of analytes was conducted on an C18 column using a mobile phase consisting of 0.1% aqueous formic acid and acetonitrile. Polymyxin B was used as an internal standard (IS). Colistin and IS were monitored in positive ion mode with the following mass transition pairs: m/z 585.6→m/z 101.4 for colistin A，m/z 578.6→m/z 101.4 for colistin B and m/z 595.6→m/z 227.2 for IS, respectively. The established method expressed good linearity in 50 – 20000 ng·mL−1 of colistin, with the lower limit of quantification (LLOQ) of 50 ng·mL−1. Methodology validations, including accuracy, precision, matrix effect, recovery, stability, and dilution integrity met the US Food and Drug Administration (FDA) acceptance criteria for bioanalytical method validation. Noncompartmental pharmacokinetic parameters were obtained by the statistical moment theory. The estimates for the terminal half-life (t1/2), the peak time (Tmax), the peak concentration (Cmax), the area under the plasma concentration-time curve (AUC0−t), the volume of distribution (V), the total body clearance (CL) and the mean residence time (MRT0−t) were calculated to be 2.53 ± 1.6 h, 2.17 ± 1.57 h, 2913.01 ± 644.89 ng·mL−1, 15153.46 ± 3599.81 h·ng·mL−1, 0.98 ± 0.56 L·kg−1, 0.28 ± 0.09 L·h−1·kg−1 and 4.07 ± 1.13 h, respectively. And the concentrations of colistin in rat kidney tissue after continuous administration for 1, 3, 5, 7 days were 1.49 ± 0.35 μg·g−1, 2.88 ± 0.74 μg·g−1, 3.40 ± 0.25 μg·g−1 and 4.33 ± 0.63 μg·g−1, respectively. The established method provided a convenient, rapid, stable, sensitive, accurate way for the determination of colistin concentration, which has been successfully used for the pharmacokinetic analysis of colistin sulfate in rat and to explore the relationship between the renal accumulation of colistin and the duration of dosing.

Evaluation of the cytochrome P450 2C19 and 3A4 inhibition potential of the complement factor 5a receptor antagonist ACT-1014-6470 in vitro and in vivo.

ACT-1014-6470 is an orally available complement factor 5a receptor 1 antagonist and a novel treatment option in autoinflammatory diseases. The in vitro inhibition potential of ACT-1014-6470 on cytochrome P450 isozymes (CYPs) and its effect on the pharmacokinetics (PK) of the CYP2C19 and CYP3A4 substrates omeprazole and midazolam, respectively, in humans were assessed. In vitro assays were conducted with isoform-specific substrates in human liver microsomes. In an open-label, two-period, fixed-sequence cocktail study, single doses of 20 mg omeprazole and 2 mg midazolam were administered concomitantly to 20 healthy male subjects alone (Treatment A) and after a single dose of 100 mg ACT-1014-6470 (Treatment B) under fed conditions. Safety and PK assessments were performed. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of noncompartmental PK parameters of Treatment B vs Treatment A were calculated. In vitro, no time-dependent inhibition was observed and the lowest inhibition constant of 4.3 μM ACT-1014-6470 was recorded for CYP2C19. In humans, GMRs (90% CI) of omeprazole PK were 1.9 (1.5-2.5) for maximum plasma concentration (Cmax ) and 1.9 (1.5-2.3) for area under the plasma concentration-time curve (AUC) from 0 to 12 h. Midazolam PK showed GMRs (90% CI) of 1.1 (1.1-1.2) for Cmax and 1.5 (1.4-1.6) for AUC from 0 to 24 h. All treatments were well tolerated. In line with in vitro results and regulatory risk factor calculation, the increased exposure to omeprazole and midazolam in humans after concomitant administration with a single dose of 100 mg ACT-1014-6470 reflected a weak inhibition of CYP2C19 and CYP3A4.

Pharmacokinetics of cefmetazole in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue of patients scheduled for lower gastrointestinal surgery: Dosing considerations based on site-specific pharmacodynamic target attainment

IntroductionCefmetazole (CMZ) has gained interest as a carbapenem-sparing alternative to the epidemic of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales (ESBL-E). In this study, we investigated the pharmacokinetics (PK) of CMZ in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue to assess the dosing regimen needed to achieve pharmacodynamic (PD) goals at the target site. MethodsPatients scheduled for elective lower gastrointestinal surgery were intravenously administered CMZ. Plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue samples were collected after CMZ infusion and during the surgery, and CMZ concentrations were measured. The non-compartmental and compartmental PK parameters were estimated and used to evaluate site-specific PD target attainment. ResultsA total of 38 plasma, 27 peritoneal fluid, 36 peritoneum, and 38 subcutaneous adipose tissue samples were collected from 10 patients. The non-compartmental PK analysis revealed the ratios of the mean area under the drug concentration-time curve (AUC0–3.5 h) of peritoneal fluid-to-plasma, peritoneum-to-plasma, and subcutaneous adipose tissue-to-plasma were 0.60, 0.36, and 0.11, respectively. The site-specific PD target attainment analyses based on the breakpoints for ESBL-E per the Japanese surgical site infection (SSI) surveillance (MIC90 = 8 mg/L) revealed that 2 g CMZ every 3.5 h achieved desired bactericidal effect at all sites and 2 g CMZ every 6 h achieved PD goals at peritoneum and peritoneal fluid. ConclusionThese findings clarify the PK of CMZ in abdominal tissues and could help decide optimal dosing regimens to treat intra-abdominal infection and prophylaxis of SSI.

Ceftolozane-Tazobactam Pharmacokinetics in the Abdominal Tissue of Patients Undergoing Lower Gastrointestinal Surgery: Dosing Considerations Based on Site-Specific Pharmacodynamic Target Attainment.

Recently, complicated intra-abdominal infections (cIAI) have been caused not only by Escherichiacoli, Klebsiellapneumoniae, Enterobacter cloacae, and Pseudomonasaeruginosa, but also by extended-spectrum β-lactamase-producing Enterobacterales members. Ceftolozane-tazobactam (CTLZ-TAZ) is considered to exhibit therapeutic effects against cIAI. Studies on the concentrations of antibiotics in abdominal tissues directly affected by cIAI are limited. Therefore, in this study, we investigated the pharmacokinetics of CTLZ-TAZ in abdominal tissue and simulated the administration regimen required to achieve the pharmacodynamic target for cIAI-causing bacteria. Patients scheduled for elective lower gastrointestinal surgery were intravenously administered preoperative CTLZ-TAZ (1g CTLZ and 0.5g TAZ). Plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue samples were collected during the surgery, and CTLZ as well as TAZ concentrations were measured. The noncompartmental and compartmental pharmacokinetic parameters were then estimated. Site-specific pharmacodynamic target attainment analysis using 1.5g of CTLZ-TAZ was performed. CTLZ-TAZ was administered to nine patients (once to five patients and twice to four patients). The mean peritoneal fluid-to-plasma ratio (one dose/two doses) for CTLZ was 0.74/1.15, which was slightly higher than the mean peritoneal fluid-to-plasma ratio for TAZ (0.95/1.13). The ratio for subcutaneous adipose was lower than those for peritoneal fluid and peritoneum tissues. We also discovered that the average ratio of CTLZ and TAZ concentrations in all tissues was maintained at or above 2:1. In our investigation of pharmacodynamic target attainment in each tissue, the desired bactericidal effect was attained with all CTLZ-TAZ (1.5g) administration regimens [q12h (3g/day), q8h (4.5g/day), and q6h (6g/day)]. To the best of our knowledge, this is the first study investigating the optimal pharmacodynamic level of CTLZ-TAZ in the abdominal tissue against cIAI-causing bacteria. This study also serves as a guideline for designing an optimal administration regimen based on pharmacodynamic target attainment for cIAI-causing bacteria. The institutional review board of Hiroshima University Hospital, CRB6180006. The Japan Registry of Clinical Trials, jRCTs061190025.

Noncompartmental pharmacokinetics of three intravenous mycophenolate mofetil concentrations in healthy Standardbred mares.

Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid (MPA) which acts as an immunosuppressive agent. During the biotransformation of MMF to MPA, additional metabolites including MPA phenol glucuronide (MPAG), MPA acyl glucuronide (AcMPAG) and MPA phenol glucoside (MPG) are formed. To define the noncompartmental pharmacokinetic (PK) parameters of three single doses of intravenous (i.v.) MMF and its downstream metabolites in healthy horses. Six healthy Standardbred mares. Generic MMF (Par Pharmaceuticals; Chestnut Ridge, NY, USA) was reconstituted and administered as a single i.v. bolus at 1.0 mg/kg, 5.0 mg/kg and 10.0 mg/kg with an eight day washout between treatments. Blood samples were collected immediately before MMF administration and over 24 h. A liquid chromatography-tandem mass spectrometry assay was developed following FDA guidance to determine plasma MMF, MPA, MPAG, AcMPAG and MPG concentrations. Plasma concentrations were analysed independently, followed by calculation of geometric mean and coefficient of variation. Noncompartmental PK parameters were determined for MMF and all metabolites at all doses. MMF was rapidly converted to MPA in all horses. Each incremental dose of MMF resulted in increases in Cmax and AUCinf _obs for MPA and the three additional metabolites. Within the 10-fold dose range, the increase in Cmax and AUCinf _obs for MMF and its metabolites was nonlinear. Horses biotransform MMF into MPA, MPAG, AcMPAG and MPG via the glucuronidation and glucosidation clearance pathways. Equine reference PK profiles for MPA and the metabolites, MPAG, AcMPAG and MPG were established.

Improvement in Bioavailability and Pharmacokinetic Characteristics of Efavirenz with Booster Dose of Ritonavir in PEGylated PAMAM G4 Dendrimers.

Efavirenz (EFV) with a booster dose of ritonavir (RTV) (EFV-RTV) inhibits the metabolism of EFV and improves its bioavailability. However, inadequate organ perfusion with surface permeability glycoprotein (P-gp) efflux sustains the viable HIV. Hence, the present investigations were aimed to evaluate the pharmacokinetics and tissue distribution efficiency of EFV by encapsulating it into PEGyalated PAMAM (polyamidoamine) G4 dendrimers with a booster dose of RTV (PPG4ER). The entrapment efficiency of PEGylated PAMAM G4 dendrimers was found to be 94% and 92.12% for EFV and RTV respectively with a zeta potential of 0.277mV. The pharmacokinetics and tissue distribution behavior of EFV within PPG4ER was determined by developing and validating a simple, sensitive, and reliable bioanalytical method of RP-HPLC. The developed bioanalytical method was very sensitive with a quantification limit of 18.5ng/ml and 139.2ng/ml for EFV and RTV, respectively. The comparative noncompartmental pharmacokinetic parameters of EFV were determined by administrating a single intraperitoneal dose of EFV, EFV-RTV, and PPG4ER to Wistar rats. The PPG4ER produced prolonged release of EFV with a mean residential time (MRT) of 24h with Cmax 7.68µg/ml in plasma against EFV-RTV with MRT 11h and Cmax 3.633µg/ml. The PPG4ER was also detected in viral reservoir tissues (lymph node and spleen) for 3-4days, whereas free EFV and EFV-RTV were cleared within 72h. The pharmacokinetic data including Cmax, t1/2, AUCtot, and MRT were significantly improved in PPG4ER as compared with single EFV and EFV-RTV. This reveals that the PPG4ER has great potential to target the virus harbors tissues and improve bioavailability.

Pharmacokinetics of Orally Administered Prednisolone in Alpacas.

This study aimed to determine the pharmacokinetics of prednisolone following intravenous and oral administration in healthy adult alpacas. Healthy adult alpacas were given prednisolone (IV, n = 4), as well as orally (PO, n = 6). Prednisolone was administered IV once (1 mg/kg). Oral administration was once daily for 5 days (2 mg/kg). Each treatment was separated by a minimum 4 month washout period. Samples were collected at 0 (pre-administration), 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, and 24 h after IV administration, and at 0 (pre-administration), 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, 24 after the first and 5th PO administration. Samples were also taken for serial complete blood count and biochemistry analysis. Prednisolone concentration was determined by high pressure liquid chromatography. Non-compartmental pharmacokinetic parameters were then determined. After IV administration clearance was 347 mL/kg/hr, elimination half-life was 2.98 h, and area under the curve was 2,940 h*ng/mL. After initial and fifth oral administration elimination half-life was 5.27 and 5.39 h; maximum concentration was 74 and 68 ng/mL; time to maximum concentration was 2.67 and 2.33 h; and area under the curve was 713 and 660 hr*ng/mL. Oral bioavailability was determined to be 13.7%. Packed cell volume, hemoglobin, and red blood cell counts were significantly decreased 5 days after the first PO administration, and serum glucose was significantly elevated 5 days after the first PO administration. In conclusion, serum concentrations of prednisolone after IV and PO administration appear to be similar to other veterinary species. Future research will be needed to determine the pharmacodynamics of prednisolone in alpacas.

The LC-MS/MS-Based Measurement of Isopimaric Acid in Rat Plasma and Application of Pharmacokinetics.

Isopimaric acid (IPA) exhibits a diverse array of pharmacological activities, having been shown to function as an antihypertensive, antitumor, antibacterial, and hypocholesterolemic agent. However, few studies of the pharmacokinetics of IPA have been performed to date, and such analyses are essential to explore the in vivo mechanisms governing the biological activity of this compound. As such, we herein designed a selective LC-MS approach capable of quantifying serum IPA levels in model rats using an Agilent HC-C18 column (250 mm × 4.6 mm, 5 μm) via isocratic elution with a mobile phase composed of methanol 0.5% formic acid (91 : 9, v/v) at a 1 mL/min flow rate. Ion monitoring at m/z 301.2 [M-H]− was used to quantify IPA levels in plasma samples from these rats, while internal standard (IS) levels were assessed at m/z 455.3 [M-H]−. After validation, this approach was employed to conduct a pharmacokinetic analysis of rats administered IPA via the oral (p.o. 50, 100, or 200 mg/kg) and intravenous (i.v. 5 mg/kg) routes. Analyses of noncompartmental pharmacokinetic parameters revealed that IPA underwent secondary absorption following oral administration to these animals, with the two tested oral doses (50 and 100 mg/kg) being associated with respective absolute bioavailability values of 11.9% and 17.5%. In summary, this study may provide a foundation for future efforts to explore the mechanistic basis for the pharmacological activity of IPA, offering insights to guide its subsequent clinical utilization.

Quantification and Pharmacokinetics Study of Pedunculoside in Rats by Using UPLC-MS/MS

Background: Pedunculoside (PE) is a triterpene saponin from the barks of Ilex rotunda, a Traditional Chinese Medicine called Jiubiying, which is used for the treatment of cold and fever, tonsillitis, sore throat, acute and chronic hepatitis, etc. Previous studies have confirmed that crude extract orally has a significant therapeutic effect on myocardial infarction. Methods: A simple, sensitive, and specific method by using UPLC-MS/MS to study the pharmacokinetics of PE in rats was developed and validated, with ilexsaponin A as an internal standard. Methanol was used as a protein precipitation reagent for blood sample extraction. A Waters Acquity C18 column (2.1 mm × 50 mm, 1.7 μm) was used for chromatographic separation with a gradient elution of CH3CN: 0.1% formic acid (0.3 mL·min-1). Negative ion electrospray ionization was used for detection in multiple reaction monitoring mode. Results: PE was linear within the concentration range of 0.14-1118.00 ng/mL. The LLOQ was 0.14 ng/mL for the plasma samples. The intra-day and inter-day precision were ranged from 1.18% to 10.48%, while the accuracy ranged from -1.32% to 1.68%, indicating satisfactory precision and accuracy of the assay. The extraction recoveries for PE and IS were ranged from 81.40% to 86.65%, with no significant variation among the three concentrations, respectively. PE remained stable at room temperature (25°C) for 3 h, in auto-sampler (4°C) for 24 h, after three freeze-thaw cycles, and in long-term storage at ‒20°C for 30 days. The PK results of PE indicated its poor oral bioavailability (3.37%). Conclusion: Non-compartmental pharmacokinetics parameters indicated that PE was rapidly distributed to the tissues and metabolized. The pharmacokinetic data of this paper highlighted the first-time report of PE oral bioavailability with two different administration manners, which will help to better understand how PE metabolized in rats and exert its pharmacological effect in vivo.