Standard Non-compartmental Analysis Research Articles

Model-Based Bioequivalence Analysis to Assess and Predict the Relative Bioavailability of Valproic Acid Formulations.

Model-based bioequivalence (MBBE) encompasses the use of nonlinear mixed effect models supporting the estimation of pharmacokinetic endpoints to assess the relative bioavailability between multi-source drug products. This application emerges as a valuable alternative to the standard non-compartmental analysis (NCA) in bioequivalence (BE) studies in which dense sampling is not possible. In this work, we aimed to assess the application of MBBE compared to traditional methods in evaluating the relative bioavailability of two formulations with different drug release properties. Additionally, we sought to predict the performance of a modified-release formulation in a multiple-dose scenario, leveraging data from a single-dose study. MBBE analysis was implemented to estimate the BE endpoints (90%CI for the Test/Reference geometric mean ratio, T/R GMR) in area under the concentration-time curve (AUC) and maximum concentration (Cmax) using data from a single-dose, 2-period, 2-sequence BE study performed in 14 healthy subjects between a locally developed valproic acid extended-release formulation (Test) and the brand-name delayed-release formulation (Reference). Results were compared with the standard approach, revealing that MBBE analysis achieved higher discrimination between formulations for Cmax, addressing limitations of the experimental sampling design and highlighting an advantage for this model-based analysis even when rich data are available. Additionally, the bioequivalence outcome under the multiple-dose scenario was predicted through a simulation-based study for both total and unbound valproic acid concentrations, considering the impact of valproic acid saturable binding on BE conclusions. The MBBE analysis was superior to the NCA approach in detecting product-related differences, overcoming limitations in the study experimental design. Predictions for the multiple-dose scenario preclude that the extended-release properties of the Test formulation would persist at steady state, resulting in lower peak-to-trough fluctuation and bioequivalent performance in terms of the extent of drug absorption. Overall, these results should discourage unnecessary experimentation in healthy subjects.

Pharmacokinetics and Biodistribution of 16,16 dimethyl Prostaglandin E2 in Non-Irradiated and Irradiated Mice and Non-Irradiated Non-Human Primates.

Exposure to high-dose ionizing radiation can lead to life-threatening injuries and mortality. Bone marrow is the most sensitive organ to radiation damage, resulting in the hematopoietic acute radiation syndrome (H-ARS) with the potential sequelae of infection, hemorrhage, anemia, and death if untreated. The development of medical countermeasures (MCMs) to protect or mitigate radiation injury is a medical necessity. In our well-established murine model of H-ARS we have demonstrated that the prostaglandin E2 (PGE2) analog 16,16 dimethyl-PGE2 (dmPGE2) has survival efficacy as both a radioprotectant and radiomitigator. The purpose of this study was to investigate the pharmacokinetics (PK) and biodistribution of dmPGE2 when used as a radioprotector in irradiated and non-irradiated inbred C57BL/6J mice, PK in irradiated and non-irradiated Jackson Diversity Outbred (JDO) mice, and the PK profile of dmPGE2 in non-irradiated non-human primates (NHPs). The C57BL/6J and JDO mice each received a single subcutaneous (SC) dose of 35 ug of dmPGE2 and were randomized to either receive radiation 30 min later or remain non-irradiated. Plasma and tissue PK profiles were established. The NHP were dosed with 0.1 mg/kg by SC administration and the PK profile in plasma was established. The concentration time profiles were analyzed by standard non-compartmental analysis and the metrics of AUC0-Inf, AUC60-480 (AUC from 60-480 min), Cmax, and t1/2 were evaluated. AUC60-480 represents the postirradiation time frame and was used to assess radiation effect. Overall, AUC0-Inf, Cmax, and t1/2 were numerically similar between strains (C57BL/6J and JDO) when combined, regardless of exposure status (AUC0-Inf: 112.50 ng·h/ml and 114.48 ng·h/ml, Cmax: 44.53 ng/ml and 63.96 ng/ml; t1/2: 1.8 h and 1.1 h, respectively). PK metrics were numerically lower in irradiated C57BL/6J mice than in non-irradiated mice [irradiation ratio: irradiated values/non-irradiated values = 0.71 for AUC60-480 (i.e., 29% lower), and 0.6 for t1/2]. In JDO mice, the radiation ratio was 0.53 for AUC60-480 (i.e., 47% lower), and 1.7 h for t1/2. The AUC0-Inf, Cmax, and t1/2 of the NHPs were 29.20 ng·h/ml, 7.68 ng/ml, and 3.26 h, respectively. Despite the numerical differences seen between irradiated and non-irradiated groups in PK parameters, the effect of radiation on PK can be considered minimal based on current data. The biodistribution in C57BL/6J mice showed that dmPGE2 per gram of tissue was highest in the lungs, regardless of exposure status. The radiation ratio for the different tissue AUC60-480 in C57BL/6J mice ranged between 0.5-1.1 (50% lower to 10% higher). Spleen, liver and bone marrow showed close to twice lower exposures after irradiation, whereas heart had a 10% higher exposure. Based on the clearance values from mice and NHP, the estimated allometric scaling coefficient was 0.81 (95% CI: 0.75, 0.86). While slightly higher than the current literature estimates of 0.75, this scaling coefficient can be considered a reasonable estimate and can be used to scale dmPGE2 dosing from animals to humans for future trials.

Pharmacokinetics of Moxidectin combined with Albendazole or Albendazole plus Diethylcarbamazine for Bancroftian Filariasis.

Moxidectin (MOX) is a milbemycin endectocide recently approved by the U.S. FDA for the treatment of onchocerciasis in persons at least 12 years of age. MOX has been shown to have a good safety profile in recent clinical trials. The efficacy of MOX for the treatment of lymphatic filariasis (LF) and its potential use in mass drug administration protocols for the elimination of LF is currently under evaluation. In the context of a clinical trial, we investigated the pharmacokinetics and drug interactions of a combination of MOX plus albendazole (ALB) with or without diethylcarbamazine (DEC) compared to ivermectin (IVM) plus ALB with or without DEC in the following four different treatment arms: (I) IVM (0.2mg/kg) plus DEC (6 mg/kg) and ALB (400mg); (II) IVM plus ALB; (III) MOX (8 mg) plus DEC and ALB; and (IV) MOX plus ALB. Drug concentrations were determined using validated liquid chromatography-mass spectrometric methods. Pharmacokinetic parameters were determined using standard non-compartmental analysis methods. Statistical analysis was performed using JMP software. Fifty-eight of 164 study participants (53 men and five women) were included with ages ranging from 18 to 63 yrs (mean = 37). MOX apparent oral clearance (Cl/F) ranged from 0.7 to 10.8 L/hr with Cmax values ranging from 20.8 to 314.5 ng/mL. The mean (range) area under the curve (AUC)0-∞ for MOX, 3405 ng*hr/mL (742-11376), and IVM 1906 ng*hr/mL (692-5900), varied over a ~15.3 and ~8.5-fold range, respectively. The geometric mean ratio for Cmax, AUC0-t, and AUC0-∞ were within the no-drug interaction range of 80-125% for all drugs. This indicates that the addition of MOX to ALB alone or ALB plus DEC for LF therapy did not alter the drug exposure of co-administered drugs compared to IVM combinations. Clinical Trial Registration: NCT04410406, https://clinicaltrials.gov/.

Clinical and Preclinical Single-Dose Pharmacokinetics of VIR-2218, an RNAi Therapeutic Targeting HBV Infection.

Background and ObjectiveVIR-2218 is an investigational N-acetylgalactosamine–conjugated RNA interference therapeutic in development for chronic hepatitis B virus (HBV) infection. VIR-2218 was designed to silence HBV transcripts across all genotypes and uses Enhanced Stabilization Chemistry Plus (ESC+) technology.This study was designed to evaluate the single-dose pharmacokinetics of VIR-2218 in preclinical species and healthy volunteers.MethodsPreclinically, a single subcutaneous dose of VIR-2218 (10 mg/kg) was administered to rats and nonhuman primates (NHPs), and the pharmacokinetics were assessed in plasma, urine, and liver using standard noncompartmental analysis (NCA) methods. Clinically, healthy volunteers were randomized (6:2 active:placebo) to receive a single subcutaneous dose of VIR-2218 (50–900 mg) or placebo. Pharmacokinetics were similarly assessed within human plasma and urine using NCA methods.ResultsIn rats and NHPs, VIR-2218 was stable in plasma and was converted to AS(N-1)3’VIR-2218, the most prominent circulating metabolite, at < 10% plasma exposure compared with parent. VIR-2218 rapidly distributed to the liver, reaching peak liver concentrations within 7 and 24 h in rats and NHPs, respectively. In humans, VIR-2218 was rapidly absorbed, with a median time to peak plasma concentration (tmax) of 4–7 h, and had a short median plasma half-life of 2–5 h. Plasma exposures for area under the plasma concentration–time curve up to 12 h (AUC0–12) and mean maximum concentrations (Cmax) increased in a slightly greater-than-dose-proportional manner across the dose range studied. Interindividual pharmacokinetic variability was low to moderate, with a percent coefficient of variation of < 32% for AUC and < 43% for Cmax. A portion of VIR-2218 was converted to an active metabolite, AS(N-1)3’VIR-2218, with a median tmax of 6–10 h, both of which declined below the lower limit of quantification in plasma within 48 h. The pharmacokinetic profile of AS(N-1)3’VIR-2218 was similar to that of VIR-2218, with plasma AUC0–12 and Cmax values ≤ 12% of VIR-2218. VIR-2218 and AS(N-1)3’VIR-2218 were detectable in urine through the last measured time point, with approximately 17–48% of the administered dose recovered in urine as unchanged VIR-2218 over 0–24 h postdose. Based on pharmacokinetics in preclinical species, VIR-2218 localizes to the liver and likely exhibits prolonged hepatic exposure. Overall, no severe or serious adverse events or discontinuations due to adverse events were observed within the dose range evaluated for VIR-2218 in healthy volunteers (Vir Biotechnology, Inc., unpublished data).ConclusionsVIR-2218 showed favorable pharmacokinetics in healthy volunteers supportive of subcutaneous dosing and continued development in patients with chronic HBV infection.Clinical Trial Registration NoNCT03672188, September 14, 2018.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-021-00369-w.

Prospective evaluation of high-dose methotrexate pharmacokinetics in adult patients with lymphoma usingnovel determinants of kidney function.

High‐dose methotrexate (HDMTX) pharmacokinetics (PKs), including the best estimated glomerular filtration rate (eGFR) equation that reflects methotrexate (MTX) clearance, requires investigation. This prospective, observational, single‐center study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96 h postinfusion. MTX and 7‐hydroxy‐MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine‐ or cystatin C‐based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6 years (IQR 59.2–75.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8–11.3) grams. Median clearance was similar across three dosing levels at 4.5–5.6 L/h and was consistent with linear PKs. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a fourfold range and appeared to increase in proportion to the dose. The eGFRcys (ml/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (r = 0.31 and 0.51, respectively). HDMTX as a 4‐h infusion displays high interpatient pharmacokinetic variability. Population PK modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C‐based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management.

Prospective study of Lipiodol distribution as an imaging marker for doxorubicin pharmacokinetics during conventional transarterial chemoembolization of liver malignancies.

To evaluate the prognostic potential of Lipiodol distribution for thepharmacokinetic (PK) profiles of doxorubicin (DOX) and doxorubicinol (DOXOL) after conventional transarterial chemoembolization (cTACE). This prospective clinical trial ( ClinicalTrials.gov : NCT02753881) included 30 consecutive participants with liver malignancies treated with cTACE (5/2016-10/2018) using 50mg DOX/10mg mitomycin C emulsified 1:2 with ethiodized oil (Lipiodol). Peripheral blood was sampled at 10 timepoints for standard non-compartmental analysis of peak concentrations (Cmax) and area under the curve (AUC) with dose normalization (DN). Imaging markers included Lipiodol distribution on post-cTACE CT for patient stratification into 1 segment (n = 10), ≥ 2 segments (n = 10), and lobar cTACE (n = 10), and baseline enhancing tumor volume (ETV). Adverse events (AEs) and tumor response on MRI were recorded 3-4weeks post-cTACE. Statistics included repeated measurement ANOVA (RM-ANOVA), Mann-Whitney, Kruskal-Wallis, Fisher's exact test, and Pearson correlation. Hepatocellular (n = 26), cholangiocarcinoma (n = 1), and neuroendocrine metastases (n = 3) were included. Stratified according to Lipiodol distribution, DOX-Cmax increased from 1 segment (DOX-Cmax, 83.94 ± 75.09ng/mL; DN-DOX-Cmax, 2.67 ± 2.02ng/mL/mg) to ≥ 2 segments (DOX-Cmax, 139.66 ± 117.73ng/mL; DN-DOX-Cmax, 3.68 ± 4.20ng/mL/mg) to lobar distribution (DOX-Cmax, 334.35 ± 215.18ng/mL; DN-DOX-Cmax, 7.11 ± 4.24ng/mL/mg; p = 0.036). While differences in DN-DOX-AUC remained insignificant, RM-ANOVA revealed significant separation of time concentration curves for DOX (p = 0.023) and DOXOL (p = 0.041) comparing 1, ≥ 2 segments, and lobar cTACE. Additional indicators of higher DN-DOX-Cmax were high ETV (p = 0.047) and Child-Pugh B (p = 0.009). High ETV and tumoral Lipiodol coverage also correlated with tumor response. AE occurred less frequently after segmental cTACE. This prospective clinical trial provides updated PK data revealing Lipiodol distribution as an imaging marker predictive of DOX-Cmax and tumor response after cTACE in liver cancer. • Prospective pharmacokinetic analysis after conventional TACE revealed Lipiodol distribution (1 vs. ≥ 2 segments vs. lobar) as an imaging marker predictive of doxorubicin peak concentrations (Cmax). • Child-Pugh B class and tumor hypervascularization, measurable as enhancing tumor volume (ETV) at baseline, were identified as additional predictors for higher dose-normalized doxorubicin Cmax after conventional TACE. • ETV at baseline and tumoral Lipiodol coverage can serve as predictors of volumetric tumor response after conventional TACE according to quantitative European Association for the Study of the Liver (qEASL) criteria.

Bioequivalence of Two Oral Ciprofloxacin Extended-Release Formulations in Healthy Mexican Volunteers

Introduction. Oral ciprofloxacin extended-release formulation decreases the risk of treatment failure and prevents the development of antimicrobial resistance. However, non-equivalent formulations lead to subtherapeutic plasma drug concentrations, increasing the risk of such problems. Objective. To determine the bioequivalence of two oral ciprofloxacin extended-release tablet formulations (1,000 mg) in healthy Mexican volunteers. Material and Methods. In this open-label 2 × 2 crossover design study, 26 healthy volunteers were randomly allocated to receive a single dose of the reference drug Cipro XR® (Bayer, Mexico) and the test formulation Ciproflox DM® (Senosiain Laboratories, Mexico). Blood samples were obtained for 24 hours. Ciprofloxacin plasma levels were quantified using a validated liquid chromatography method. Pharmacokinetic parameters were obtained by standard non-compartmental analysis. In order to determine bioequivalence, log-transformed test/reference ratios of Cmax, AUC0-t, and AUC0-inf were compared by an analysis of variance, followed by the 90 % confidence intervals and the Schuirmann bilateral test. Results. The 90 % confidence intervals ranged from 85.69 to 114.31 % for Cmax, 85.16-115.84 % in AUC0-t, and 85.39-114.61 % for AUC0-inf, all cases were within bioequivalence acceptance criteria (80-125 %). Schuirmann test verified the probability that the values were within these criteria (p &lt; 0.05). No side-effects were observed with any treatment. Conclusions. The results obtained demonstrate bioequivalence between the analyzed formulations.

Abstract CT092: Pharmacokinetics of a THIOMABTM antibody drug conjugate (TDC): DMUC4064A in a phase 1 study with platinum-resistant ovarian cancer

Abstract BACKGROUND: DMUC4064A is a TDC comprising a humanized anti-MUC16 IgG1 and a potent anti-mitotic agent, monomethyl auristatin E (MMAE) through a protease-labile linker through engineered cysteine at a Drug Antibody Ratio (DAR) of 2. The use of engineered cysteines is intended to allow more homogenous conjugation, which in turn can improve the overall performance of the TDC (i.e. slower clearance), compared to the conventional ADC (prepared by stochastic conjugation to interchain disulfide bond cysteines). MUC16 is a transmembrane glycoprotein overexpressed on ovarian cancer cells, which in its soluble form is known as Carbohydrate antigen 125 (CA125). A phase I study in PROC patients is ongoing to assess the safety, efficacy and PK of DMUC4064A given every 3 weeks (Q3W). METHODS: Serum/plasma samples at multiple time points were quantified for three analytes (unconjugated MMAE, DMUC4064A total antibody (tAb), and DMUC4064A conjugate (measured as antibody-conjugated MMAE, acMMAE)). The cycle 1 PK was assessed by standard non-compartmental analysis. The impact of serum CA125 on PK was investigated. RESULTS: Within the tested dose range (1.0-5.6 mg/kg), acMMAE and tAb showed nonlinear PK with more than dose-proportional exposure at the higher doses (4.8 mg/kg and 5.6 mg/kg). A clear correlation of acMMAE with tAb exposure was observed. The PK of DMUC4064A at the highest dose tested (5.6 mg/kg), as measured by acMMAE, showed a volume of distribution of approximately 52 mL/kg and a clearance of ~7 mL/day/kg with a terminal half-life of approximately 5.5 days. Unconjugated MMAE exposure was consistently lower than acMMAE with a mean Cmax approximately 150-300 fold lower than that of acMMAE. At higher doses (&amp;gt;4.0 mg/kg), unconjugated MMAE exposure was variable and overlapping across doses. Accumulation of all analytes was minimal after repeated dosing (Q3W). Based on preliminary data from this ongoing study, baseline CA125 levels have not shown any apparent impact on cycle 1 exposure. Compared to the conventional anti-MUC16 ADC (DMUC5754A, DAR 3.5) at 2.4 mg/kg (MTD), the TDC DMUC4604A at 5.6 mg/kg demonstrates a greater than 3 fold slower acMMAE clearance1. CONCLUSION: In this ongoing study of DMUC4604A, nonlinear PK of acMMAE and tAb were observed over the dose range studied, and exposures of acMMAE and tAb were highly correlated. This is the first report of clinical PK data of a TDC demonstrating slower clearance compared to a conventional ADC format. 1 Liu JF, et al. Annals of Oncology 27: 2124–2130, 2016 Citation Format: Amit Garg, Gaohong She, Ian Donatello, Matts Kagedal, Douglas D. Leipold, Ola Saad, Joyce Liu, Kathleen Moore, Erika Hamilton, Howard Burris, Judy Wang, Michael Birrer, Eric Humke, Sandhya Girish. Pharmacokinetics of a THIOMABTM antibody drug conjugate (TDC): DMUC4064A in a phase 1 study with platinum-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT092. doi:10.1158/1538-7445.AM2017-CT092

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of an Anti-Ferroportin Antibody in Patients with Anemia Due to Chronic Renal Failure

▪Introduction:The iron transporter ferroportin is a membrane protein expressed in enterocytes that absorb dietary iron, macrophages of the spleen and liver that recycle iron from old red blood cells (RBCs), and hepatocytes that store and release iron according to body needs. Hepcidin (HEPC) regulates the absorption, plasma concentrations, and tissue distribution of iron through interactions with ferroportin, leading to degradation of ferroportin.LY2928057 (LY), a humanized immunoglobulin (IgG4) monoclonal antibody, binds to ferroportin and prevents the HEPC-mediated degradation of ferroportin without affecting iron efflux.Objectives:Objectives were to assess safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of LY in patients with chronic kidney disease (CKD) on hemodialysis (HD) after intravenous (IV) multiple doses of LY.The study, compliant with Helsinki declaration, was approved by institutional ethic review board and subjects provided written informed consent prior to enrolment.Methods:CKD patients (N=21) received IV doses (300, 600, or 1000 mg every 2 weeks; total, 3 doses) of LY following discontinuation (when LY treatment was initiated) of erythropoiesis-stimulating agents (ESAs) and IV iron. Seven CKD patients received placebo.Safety assessments included: standard laboratory safety tests, vital signs, ECGs, and anti-drug antibodies.PD data comprised serum iron, transferrin saturation (TSAT), ferritin, HEPC, RBC count and hemoglobin (Hb).PK samples (up to 3 months post last dose) were assayed using a validated enzyme-linked immunosorbent assay method.LY PK data were analyzed using standard non-compartmental PK analysis. Summary statistics were used to describe LY PD data (parameters and ratios relative to baseline). A Bayesian analysis of the absolute change in Hb at week 6 relative to baseline was performed with the following success criterion: >60 % posterior probability of ≥0.8 g/dL difference between any LY dose group and placebo.Results - SafetyCKD patients (19 of 28 were male), with mean (SD) age and weight of 53.6 (8) years and 87.35 (18) kg, participated. LY was well tolerated; serious adverse events (syncope, anemia, hypertension, respiratory failure/staphylococcal sepsis/pneumonia) were reported by 3 patients. These were not attributed to study drug.Results - PharmacokineticsLY maximum concentrations were generally measured at the end of the 30-min infusion and concentrations decreased thereafter in a multiexponential manner. LY area under the concentration time curve (AUC or exposure) increased greater than dose proportionally from 300 to 600 mg and was roughly dose proportional from 600 to 1000 mg. This observation is consistent with binding, target-mediated clearance.LY volume of distribution was small (mean 4L) and LY clearance was low (mean 0.09 L/h) in the 600 to 1000 mg dose range, leading to a mean terminal half-life of 8 days (ranging from 5.5 to 13 days).The dosing of LY during HD did not significantly alter LY exposure.Results - PharmacodynamicsA dose-related increase in iron, with a maximum effect approximately 24 h after dose, was observed. Iron values returned to baseline in approximately 2-weeks post-LY dose. Concurrently, an increase in TSAT was observed (Figure 1).In addition, a decrease in ferritin levels was observed (Figure 2, after third dose, approximately 12% and 20% decrease relative to baseline at the 600 and 1000 mg doses, respectively).HEPC levels increased following LY administration. This is likely explained by the feed-back regulatory response of the body to the iron increase.Figure 3 illustrates that RBC and Hb declined to a lesser extent with LY 600 mg and 1000 mg dose levels compared to 300 mg dose levels and placebo treatment. The Bayesian analysis determined a posterior probability of 58% (less than 60%), for a greater than 0.8 g/dL difference between LY treatment and placebo, in the absolute change in Hb at week 6 relative to baselineConclusionLY in CKD patients was well tolerated; no safety signals or trends were identified.Expected changes in PD markers (serum iron, HEPC, TSAT, ferritin, RBC, and Hb) were observed after LY administration; however, the effect on Hb did not meet the pre-defined success criterion. It is possible that co-administration of an ESA with LY is required for the increased iron to be optimally used for Hb synthesis in RBC. [Display omitted] [Display omitted] [Display omitted] DisclosuresBarrington:Eli Lilly and Company: Employment, Equity Ownership. Sheetz:Eli Lilly and Company: Employment, Equity Ownership. Callies:Eli Lilly and Company: Employment, Equity Ownership. Waters:Eli Lilly and Company: Employment. Berg:Eli Lilly and Company: Employment, Equity Ownership. Pappas:Eli Lilly and Company: Employment. Marbury:Olando Clinical Research Center: Employment, Equity Ownership. Berg:Davita Clinical Research: Employment, Other: Full time employee of Davita Clinical Research, one of the research sites.

Multiple-Ascending-Dose Pharmacokinetics and Safety Evaluation of Baicalein Chewable Tablets in Healthy Chinese Volunteers.

Baicalein, a flavonoid isolated from the root of Scutellaria baicalensis Georgi, is a neuroprotective agent under development to treat Parkinson's disease. This study investigated the pharmacokinetics, safety and tolerability of baicalein after a multiple-ascending-dose protocol in healthy Chinese volunteers. In this single-center, double-blind, placebo-controlled, parallel-group study, participants were randomized to receive baicalein (n=8 per dose regimen) or placebo (n=2 per dose regimen). Dosing regimens were 200, 400, and 800mg once daily on days 1 and 10, twice daily on days 3-9. Plasma, urine, and feces samples were assayed for baicalein and its predominant metabolite baicalin using validated HPLC-MS/MS methods. Pharmacokinetic parameters were computed using standard non-compartmental analysis. Dose proportionality was assessed with a method combining equivalence criterion and power model. Drug safety and tolerability were assessed by monitoring adverse events and laboratory parameters. Thirty-three of 36 enrolled participants completed the study. A total of 44 adverse events occurred in 23 participants. A steady-state concentration of analytes in plasma was achieved on day 8 after repeated dosing. Analytes concentrations and exposure increased with increasing dose. The dose proportionality constant (β) for AUCss of baicalein and baicalin was 0.922 (90% confidence interval, 0.650-1.195) and 0.942 (90% confidence interval, 0.539-1.345), respectively. The accumulation index varied from 1.66 to 2.07 for baicalein and from 1.68 to 2.45 for baicalin. In dose range of 200-800mg, multiple-dose oral baicalein administration was safe and well tolerated, dose proportionality was inconclusive, and no serious accumulation of baicalein was observed.

Cefoxitin Plasma and Subcutaneous Adipose Tissue Concentration in Patients Undergoing Sleeve Gastrectomy

PurposeAntibiotic dosing in obese surgical patients has not been adequately evaluated. The objective of this study was to identify whether currently prescribed doses of cefoxitin achieve adequate and sustained plasma and tissue concentrations in obese patients undergoing sleeve gastrectomy. MethodsA prospective evaluation of plasma and tissue cefoxitin concentrations in patients undergoing sleeve gastrectomy was performed. On the day of the surgical procedure, venous blood samples (5 mL) were collected just before cefoxitin administration and then at 5, 30, 60, 120, and 240 minutes after dose administration. In addition, subcutaneous adipose tissue was collected from the surgical site at the time of surgical incision and at closure. Cefoxitin concentrations in the collected samples were quantified by using an HPLC–ultraviolet method. A standard noncompartmental analysis was performed for each individual cefoxitin plasma concentration–time profile. In addition, the ratio of tissue to plasma concentration was calculated for all patients. FindingsPlasma and tissue pharmacokinetics of cefoxitin were evaluated in 6 patients undergoing sleeve gastrectomy. The mean age and BMI were 48.7 (6.2) years and 42.8 (7.1) kg/m2, respectively. At the time of surgical closure, subcutaneous adipose tissue concentrations of cefoxitin were subtherapeutic (<8 µg/mL) in all evaluated patients. ImplicationsCurrent dosing strategies for cefoxitin in obese surgical patients may be inadequate, and there is an urgent need to define the appropriate dosage.

Small Quaternary Inhibitors K298 and K524: Cholinesterases Inhibition, Absorption, Brain Distribution, and Toxicity.

Inhibitors of acetylcholinesterase (AChE) may be used in the treatment of various cholinergic deficits, among them being myasthenia gravis (MG). This paper describes the first in vivo data for promising small quaternary inhibitors (K298 and K524): acute toxicity study, cholinesterase inhibition, absorption, and blood-brain barrier penetration. The newly prepared AChE inhibitors (bis-quinolinium and quinolinium compounds) possess a positive charge in the molecule which ensures that anti-AChE action is restricted to peripheral effect. HPLC-MS was used for determination of real plasma and brain concentration in the pharmacokinetic part of the study, and standard non-compartmental analysis was performed. The maximum plasma concentrations were attained at 30 min (K298; 928.76 ± 115.20 ng/ml) and 39 min (K524; 812.40 ± 54.96 ng/ml) after i.m. Both compounds are in fact able to target the central nervous system. It seems that the difference in the CNS distribution profile depends on an active efflux system. The K524 brain concentration was actively decreased to below an effective level; in contrast, K298 progressively accumulated in brain tissue. Peripheral AChE inhibitors are still first-line treatment in the mild forms of MG. Commonly prescribed carbamates have many severe side effects related to AChE carbamylation. The search for new treatment strategies is still important. Unlike carbamates, these new compounds target AChE via apparent π-π or π-cationic interaction aside at the AChE catalytic site.

Detection, quantifications, and pharmacokinetics of ponazuril in healthy swine.

A study on pharmacokinetics of ponazuril in piglets was conducted after a single oral dose of 5.0mg/kg b.w. Plasma concentrations were measured by high-performance liquid chromatography assay with UV detector at 255-nm wavelength. Pharmacokinetic parameters were derived by use of a standard noncompartmental pharmacokinetic analysis. Samples from six piglets showed good plasma concentrations of ponazuril, which peaked at 5.83±0.94μg/mL. Mean±SD area under the plasma concentration-time curve was 1383.42±363.26h/μg/mL, and the elimination half-life was 135.28±19.03h. Plasma concentration of ponazuril peaked at 42h (range, 36-48h) after administration and gradually decreased but remained detectable for up to 33days. No adverse effects were observed during the study period. The results indicate that ponazuril was relatively well absorbed following a single dose, which makes ponazuril likely to be effective in swine.

Novel Population Pharmacokinetic Method Compared to the Standard Noncompartmental Approach to Assess Bioequivalence of Iron Gluconate Formulations

Iron-containing products are atypical in terms of their pharmacokinetic properties because iron is only removed by plasma sampling and is non-linear. This study aims to present a novel way of assessing the relative bioavailability of two sodium ferric gluconate complex (SFGC) formulations and compare this approach to a standard previously published noncompartmental approach. Data were from open-label, randomized, single-dose studies (Study 1 was parallel whereas Study 2 was crossover). Subjects with low but normal iron levels were infused IV SFGC in sucrose by GeneraMedix Inc. and/or Ferrlecit ® Injection (Watson Laboratories Inc.). In Study 1 (n=240), 125 mg was infused over 10 minutes. In Study 2 (n=29), 62.5 mg was infused over 30 minutes. Samples were assayed for total iron (TI) and transferrin-bound iron (TBI) over 36 hours (Study 1) or 72 hours (Study 2) post-dose. Studies 1 and 2 used standard noncompartmental analysis. Study 2 also used population PK (PPK) analyses with ADAPT 5®. The final model predicted SFGC area-under-the-curve (AUCpred) and maximal concentration (Cmaxpred). Analyses of variance was conducted on ln-transformed PK parameters. Ratios of means and 90% confidence intervals (CIs) were estimated. Bioequivalence was demonstrated if values were within 80-125%. For Study 1, ratios and 90% CIs for TI baseline-corrected Cmax and AUC0-36 were 100.4 (96.5 - 104.5) and 99.7 (94.2 - 105.5). For TBI, results for TI baseline-corrected Cmax and AUC0-36 were 86.8 (82.7 - 91.1) and 92.4 (85.6 - 99.7). For Study 2, a multi-compartmental model simultaneously described the PK of TI, TBI and SFGC. Ratios and 90% CIs for SFGC Cmaxpred and AUCpred were 89.9 (85.9 - 94.0) and 89.7 (85.7 - 93.9), while ratios and 90% CI obtained from the noncompartmental analysis of Study 2 did not meet BE criteria because of low power. Both the standard and PPK modeling approach suggested bioequivalence between the iron products. However, with the PPK method, less subjects were required to meet study objectives compared to the standard noncompartmental approach which required considerably more subjects (29 vs 240).

Steady-State Plasma Concentration Profile of Transdermal Rotigotine: An Integrated Analysis of Three, Open-Label, Randomized, Phase I Multiple Dose Studies

BackgroundThe dopamine agonist rotigotine is formulated in a transdermal delivery system (patch) for once-daily application. It has been reported as efficacious in the treatment of idiopathic Parkinson's disease (PD) and restless legs syndrome. ObjectiveThis article summarizes the results of 3 clinical studies conducted to characterize the 24-hour pharmacokinetic profile of rotigotine in steady state and the effect of different patch application sites on this profile. In addition, the relative bioavailability of a single, large patch versus 2 smaller patches was assessed. MethodsOne Phase I study (SP871) assessed the steady-state pharmacokinetic properties at different application sites at a rotigotine maintenance dose of 3 mg/24 hours in healthy participants. Due to tolerability issues, the steady-state pharmacokinetic properties of rotigotine at higher doses (8 mg/24 hours) was assessed in 2 Phase I studies (SP630, SP651) in early-stage PD patients. Relative rotigotine bioavailability from a 40 cm2 patch versus 2 × 20 cm2 patches (SP651) and from a 15 cm2 patch versus 1 × 5 cm2 + 1 × 10 cm2 patches (SP871) was also evaluated. Rotigotine concentrations in plasma were analyzed using a validated LC-MS/MS method. The pharmacokinetic variables were calculated using standard noncompartmental analysis. ResultsRelease of rotigotine to the skin was 31% to 62% of total drug content in the patch. Variability of rotigotine exposure was low within participants (15%) compared with the variability observed between participants (54%). Rotigotine exposure increased proportionally in the therapeutic dose range of 2 mg/24 hours to 8 mg/24 hours. Plasma concentrations at steady state were stable over the 24-hour patch-on period. Delivery via a single, large patch compared with a combination of smaller patches did not appear to influence exposure to rotigotine. Bioavailability showed some variability depending on patch application site (hip, shoulder, abdomen, flank, thigh, upper arm); the respective mean ratios for AUC ranged between 0.87 (abdomen vs flank) and 1.46 (shoulder vs thigh). ConclusionsContinuous rotigotine delivery via a once-daily transdermal patch generated stable mean steady-state 24-hour plasma concentrations in healthy participants as well as patients with early-stage PD. Doses were achieved either by application of 1 large patch or a combination of smaller patches, resulting in the same total surface area.

Model‐based analyses of bioequivalence crossover trials using the stochastic approximation expectation maximisation algorithm

In this work, we develop a bioequivalence analysis using nonlinear mixed effects models (NLMEM) that mimics the standard noncompartmental analysis (NCA). We estimate NLMEM parameters, including between-subject and within-subject variability and treatment, period and sequence effects. We explain how to perform a Wald test on a secondary parameter, and we propose an extension of the likelihood ratio test for bioequivalence. We compare these NLMEM-based bioequivalence tests with standard NCA-based tests. We evaluate by simulation the NCA and NLMEM estimates and the type I error of the bioequivalence tests. For NLMEM, we use the stochastic approximation expectation maximisation (SAEM) algorithm implemented in monolix. We simulate crossover trials under H(0) using different numbers of subjects and of samples per subject. We simulate with different settings for between-subject and within-subject variability and for the residual error variance. The simulation study illustrates the accuracy of NLMEM-based geometric means estimated with the SAEM algorithm, whereas the NCA estimates are biased for sparse design. NCA-based bioequivalence tests show good type I error except for high variability. For a rich design, type I errors of NLMEM-based bioequivalence tests (Wald test and likelihood ratio test) do not differ from the nominal level of 5%. Type I errors are inflated for sparse design. We apply the bioequivalence Wald test based on NCA and NLMEM estimates to a three-way crossover trial, showing that Omnitrope®; (Sandoz GmbH, Kundl, Austria) powder and solution are bioequivalent to Genotropin®; (Pfizer Pharma GmbH, Karlsruhe, Germany). NLMEM-based bioequivalence tests are an alternative to standard NCA-based tests. However, caution is needed for small sample size and highly variable drug.

Pharmacokinetics of ponazuril after oral administration to healthy llamas (Lama glama)

To determine the pharmacokinetics after oral administration of a single dose of ponazuril to healthy llamas. 6 healthy adult llamas. Ponazuril (20 mg/kg) was administered once orally to 6 llamas (day 0). Blood samples were obtained on days 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 14, 21, 28, 35, 42, and 49. Serum ponazuril concentrations were determined by use of a validated reverse-phase high-performance liquid chromatography assay with UV absorbance detection. Pharmacokinetic parameters were derived by use of a standard noncompartmental pharmacokinetic analysis. Mean ± SD area under the serum concentration-time curve was 7,516 ± 2,750 h•mg/L, maximum serum ponazuril concentration was 23.6 ± 6.0 mg/L, and the elimination half-life was 135.5 ± 16.7 hours. Serum concentration of ponazuril peaked at 84 hours (range, 48 to 120 hours) after administration and gradually decreased but remained detectable for up to 35 days after administration. No adverse effects were observed during the study period. The rate and extent of absorption following oral administration of a single dose of ponazuril were sufficient to result in potentially effective concentrations, and the drug was tolerated well by llamas. At this dose, ponazuril resulted in serum concentrations that were high enough to be effective against various Apicomplexans on the basis of data for other species. The effective ponazuril concentration that will induce 50% inhibition of parasite growth for Eimeria macusaniensis in camelids is currently unknown.

Pharmacokinetics of a combination of Δ9‐Tetrahydro‐cannabinol and celecoxib in a porcine model of hemorrhagic shock

Hemorrhagic shock involves loss of a substantial portion of circulating blood volume leading to diminished cardiac output and oxygen delivery to peripheral tissues. In situations where an immediate resuscitation cannot be provided, pharmacotherapy with a novel combination of Δ9-tetrahydro-cannabinol (THC) and celecoxib (CEL) is currently investigated as an alternative strategy to prevent organ damage. In the present study, 28 Yorkshire×Landrace pigs were used to study the pharmacokinetics of THC and CEL in an established porcine model of hemorrhagic shock. Pigs in hemorrhagic shock received 0.5, 1 or 4 mg/kg THC and 2 mg/kg CEL, while normotensive pigs received 1 mg/kg THC and 2 mg/kg CEL by intravenous injection. THC and CEL plasma concentrations were simultaneously determined by LC-MS/MS. Pharmacokinetic parameters and their between animal variability were obtained using standard non-compartmental analysis as well as a compartmental analysis using nonlinear mixed effects modeling. The concentration-time profiles of THC and CEL followed a multi-exponential decline and their pharmacokinetics were similar in hemorrhagic shock and normotensive conditions, despite the substantial change in hemodynamics in the animals with shock. This interesting finding might be due to the pharmacologic effect of the THC/CEL combination, which is intended to maintain adequate perfusion of vital organs in shock. Overall, this study established THC and CEL pharmacokinetics in a porcine shock model and provides the basis for dose selection in further studies of THC and CEL in this indication.

Power estimation using a population pharmacokinetics model with optimal design by clinical trial simulations: application in pharmacokinetic drug–drug interaction studies

The aim of this article was to determine the power for pharmacokinetic interaction investigations using population a pharmacokinetic modelling approach with optimal sampling designs and clinical trial simulations. A clinical trial simulation approach was proposed to estimate the power for pharmacokinetic effects in drug-drug interaction (DDI) studies. This approach consisted of: (1) population pharmacokinetic (PK) model(s) was characterised for the drug(s) studied; (2) D-optimal design strategy was applied based on these model(s) to determine optimal sampling times for DDI investigation; (3) clinical trial simulations under particular study designs, for example a randomised parallel design, were used to evaluate the sample size needed for studying PK interaction. The approach was described using an example investigating the impact of a new anti-inflammatory drug on methotrexate (MTX) exposure in rheumatoid arthritis (RA) patients. The power for evaluating PK interaction largely depended on the interindividual variability (IIV) in PK parameters. Residual variability was also influential to a lesser degree in the sample size determination using the proposed approach. It required 40-60 participants for scenarios where IIV was relatively low in order to achieve 90% power. However, a sample size of 80 individuals was required to reach 90% power where both IIV and residual variances were high. Under the same IIV assumptions, the proposed approach in general required a smaller sample size compared with the standard noncompartmental analysis method with intensive blood samples to attain the target power. When IIV was low, the difference in the power between the two approaches was relatively small. Population PK modelling with optimal design and clinical trial simulation to determine sample size when designing drug-drug interaction studies was efficient and cost effective.

Prospective monitoring of cefepime in intensive care unit adult patients

IntroductionCefepime has been associated with a greater risk of mortality than other beta-lactams in patients treated for severe sepsis. Hypotheses for this failure include possible hidden side-effects (for example, neurological) or inappropriate pharmacokinetic/pharmacodynamic (PK/PD) parameters for bacteria with cefepime minimal inhibitory concentrations (MIC) at the highest limits of susceptibility (8 mg/l) or intermediate-resistance (16 mg/l) for pathogens such as Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. We examined these issues in a prospective non-interventional study of 21 consecutive intensive care unit (ICU) adult patients treated with cefepime for nosocomial pneumonia.MethodsPatients (median age 55.1 years, range 21.8 to 81.2) received intravenous cefepime at 2 g every 12 hours for creatinine clearance (CLCr) ≥ 50 ml/min, and 2 g every 24 hours or 36 hours for CLCr < 50 ml/minute. Cefepime plasma concentrations were determined at several time-points before and after drug administration by high-pressure liquid chromatography. PK/PD parameters were computed by standard non-compartmental analysis.ResultsSeventeen first-doses and 11 steady states (that is, four to six days after the first dose) were measured. Plasma levels varied greatly between individuals, from two- to three-fold at peak-concentrations to up to 40-fold at trough-concentrations. Nineteen out of 21 (90%) patients had PK/PD parameters comparable to literature values. Twenty-one of 21 (100%) patients had appropriate duration of cefepime concentrations above the MIC (T>MIC ≥ 50%) for the pathogens recovered in this study (MIC ≤ 4 mg/l), but only 45 to 65% of them had appropriate coverage for potential pathogens with cefepime MIC ≥ 8 mg/l. Moreover, 2/21 (10%) patients with renal impairment (CLCr < 30 ml/minute) demonstrated accumulation of cefepime in the plasma (trough concentrations of 20 to 30 mg/l) in spite of dosage adjustment. Both had symptoms compatible with non-convulsive epilepsy (confusion and muscle jerks) that were not attributed to cefepime-toxicity until plasma levels were disclosed to the caretakers and symptoms resolved promptly after drug arrest.ConclusionsThese empirical results confirm the suspected risks of hidden side-effects and inappropriate PK/PD parameters (for pathogens with upper-limit MICs) in a population of ICU adult patients. Moreover, it identifies a safety and efficacy window for cefepime doses of 2 g every 12 hours in patients with a CLCr ≥ 50 ml/minute infected by pathogens with cefepime MICs ≤ 4 mg/l. On the other hand, prompt monitoring of cefepime plasma levels should be considered in case of lower CLCr or greater MICs.