Differences In Pharmacokinetics Research Articles

Impact of Clevidipine Versus Nicardipine on Time in Range when Lowering Blood Pressure.

Background: Two intravenous medications commonly used as first-line therapy for rapid blood pressure control are nicardipine and clevidipine, both of which are available as titratable infusions. Despite pharmacokinetic differences, no data clearly support a preferred agent. Objective: To evaluate efficacy and safety outcomes associated with current use of these medications across a variety of indications in a hospital system. Methods: This study was a multi-center, retrospective chart review conducted within a hospital system from June 1, 2020 to June 30, 2021. Records of patients were matched in a one-to-one fashion based on indication for blood pressure control and similar pre-intervention blood pressure. The primary outcome was time within target blood pressure range. Results: A total of 569 patients were screened, resulting in 100 matched pairs. The percent of time in blood pressure range was similar between nicardipine and clevidipine when stratified by location of care (51.5% vs 51.7%, P = 0.970 for ED; 68.1% vs 68.8%, P = 0.913 for ICU). Overall, the median (IQR) time to target blood pressure range was significantly faster with clevidipine than nicardipine [20 (7-43) min. vs 34 (14.5-57) min., resp.; P = 0.013). There were numerically higher rates of hypotension with nicardipine than clevidipine, but this finding was not significant (17% vs 10%; P = 0.093). Conclusions: This study shows a statistically significant difference in time to target blood pressure range with clevidipine compared to nicardipine. Although there was no difference in the percentage of time in blood pressure range, nicardipine was associated with a non-significant increase in the incidence of hypotension.

Determination of monocrotaline and usaramine in rat plasma by UPLC-MS/MS and their pharmacokinetics

AbstractAn ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the determination of monocrotaline and usaramine in rat plasma, to study the plasma drug concentration and pharmacokinetics, and to calculate the absolute bioavailability. The plasma was treated with acetonitrile and methanol (9:1, v/v) protein precipitation method. The chromatographic column was UPLC HSS T3 (50 mm × 2.1 mm, 1.7 μm), the mobile phase was methanol-water (containing 0.1% formic acid with 10 mM ammonium acetate in water), and the elution time was 4 min at a flow rate of 0.4 mL min−1. Electrospray ionization (ESI) positive ion mode was used for detection and multiple reaction monitoring (MRM) mode was used for quantitative analysis. Monocrotaline and usaramine were administered sublingual intravenously (iv) 1 mg kg−1 and orally (po) 5 mg kg−1, respectively, with 6 rats in each group, for a total of 24 rats. Then the pharmacokinetic differences in rats were evaluated. For the UPLC-MS/MS method, the calibration curve showed good linearity in the range of 2–2,000 ng mL−1, where r was greater than 0.99. The precision, accuracy, recovery, matrix effect and stability results were all consistent with the requirements of biological sample detection methods. to provide scientific experimental basis for the basic research The bioavailability of monocrotaline and usaramine in rat plasma was calculated, which was 43.5 and 19.5%, respectively.

Metabolic profiling and pharmacokinetic studies of alkamides, a pair of cis-trans isomers N-isobutyl-2E,4E,8Z,10E/Z-dodecatetraenamide, from Asari Radix et Rhizoma by UHPLC-Q/TOF-MS and UHPLC-MS/MS

Cis-trans isomers of N-isobutyl-2E,4E,8Z,10E-dodecatetraenamide (DDA-E) and N-isobutyl-2E,4E,8Z,10Z-dodecatetraenamide (DDA-Z) are representative alkamides with numbness of tongue, anti-inflammatory and analgesic activities of Asari Radix et Rhizoma. However, their respective metabolic pathways and pharmacokinetic behaviors are still unknown. This study aim to investigate the metabolism of the two alkamides in vitro and in vivo using ultra-high-performance liquid chromatography-quadruple-time-of-flight mass spectrometry. Furthermore, a rapid, sensitive, and selective ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed to quantify DDA-E/Z in rat plasma. Results indicated that DDA-E and DDA-Z showed significant differences in metabolism and pharmacokinetics. Across all samples, 24 metabolites of DDA-E and 21 metabolites of DDA-Z were detected. A variety of pathways were involved in the production of these metabolites, mainly hydroxylation and oxidation. The linear range of DDA-E/Z was 1–2500 ng/mL (R2 = 0.9984), and the lowest quantification limit was 1 ng/mL. Precision, accuracy, extraction recovery, matrix effect, and stability of DDA-E/Z were within acceptable limits. Pharmacokinetic research was conducted using male Sprague-Dawley rats receiving intravenous (1 mg/kg) or intragastric (40 mg/kg) administration of DDA-E or DDA-Z solution. There was a calculated absolute bioavailability of 15.67 % for DDA-E and 4.83 % for DDA-Z when consumed orally. The apparent volume of distribution of intravenous and intragastric administrations were 4.44 ± 0.41 L/kg and 5.18 ± 0.67 L/kg for DDA-E, and 1.56 ± 1.66 L/kg and 2.35 ± 0.42 L/kg for DDA-Z. The maximal plasma concentrations of DDA-E and DDA-Z were 599.84 ± 149.92 nM and 422.09 ± 69.17 nM, and the time to maximum peak were 4.33 ± 3.51 h and 0.70 ± 1.12 h, respectively. In conclusion, in subsequent pharmacodynamics and safety evaluation studies, great attention should be paid to the metabolic characteristics and pharmacokinetic differences between DDA-E and DDA-Z.

Disease-specific differences in pharmacokinetics of paromomycin and miltefosine between post-kala-azar dermal leishmaniasis and visceral leishmaniasis patients in eastern Africa.

Treatment regimens for post-kala-azar dermal leishmaniasis (PKDL) are usually extrapolated from those for visceral leishmaniasis (VL), but drug pharmacokinetics (PK) can differ due to disease-specific variations in absorption, distribution, and elimination. This study characterized PK differences in paromomycin and miltefosine between 109 PKDL and 264 VL patients from eastern Africa. VL patients showed 0.55-fold (95%CI: 0.41-0.74) lower capacity for paromomycin saturable reabsorption in renal tubules, and required a 1.44-fold (1.23-1.71) adjustment when relating renal clearance to creatinine-based eGFR. Miltefosine bioavailability in VL patients was lowered by 69% (62-76) at treatment start. Comparing PKDL to VL patients on the same regimen, paromomycin plasma exposures were 0.74-0.87-fold, while miltefosine exposure until the end of treatment day was 1.4-fold. These pronounced PK differences between PKDL and VL patients in eastern Africa highlight the challenges of directly extrapolating dosing regimens from one leishmaniasis presentation to another.

Multiple-Dose Pharmacokinetics and Safety of Mitragynine, the Major Alkaloid of Kratom, in Rats.

This study reports the steady-state pharmacokinetic parameters for mitragynine and characterizes its elimination in male and female rats. Four male and female rats were dosed q12h with 40 mg/kg, and orally administered mitragynine for 5 and 6 days, respectively. Using a validated ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method, the plasma concentrations of mitragynine, its metabolites (7-hydroxymitragynine, 9-hydroxycorynantheidine, and mitragynine acid), and a non-CYP oxidation product (3-dehydromitragynine) were determined at various time points. Sex differences in pharmacokinetics were observed, with females demonstrating significantly higher systemic exposure of mitragynine than males. The mitragynine area under the curve normalized by the dose interval (AUC/τ) was 6741.6 ± 869.5 h*ng/mL in female rats and 1808.9 ± 191.3 h*ng/mL in males (p < 0.05). Both sexes produced similar metabolite profiles; the major metabolites were mitragynine acid and 9-hydroxycorynantheidine. 7-Hydroxymitragynine was a minor metabolite. However, higher exposure (AUCs) and the maximum plasma concentrations (C max) of active metabolites, 7-hydroxymitragynine and 9-hydroxycorynantheidine, were observed in female rats and exhibited substantial sex differences. Renal clearance of mitragynine (CLr) was low (0.64 ± 0.3 mL/h in males and 0.98 ± 0.4 mL/h in females), and unchanged mitragynine accounted for <1% of the dose excreted in feces (both sexes). The clinical chemistry, complete blood count, and hematological test results reported no abnormal hematological findings after multiple dosing in either sex.

Efficacy and acceptability of long-acting antipsychotics in acutely ill individuals with schizophrenia-spectrum disorders: A systematic review and network meta-analysis

To assess the effect of Long-acting injectable (LAI) antipsychotics in acutely ill patients, we systematically searched major databases for randomized controlled trials (RCTs) comparing LAIs with other LAIs, oral antipsychotics, or placebo in acutely symptomatic adults with schizophrenia-spectrum disorders. Data were analyzed with a random-effects network meta-analysis. Co-primary outcomes were efficacy (mean change in psychopathology rating scales) and acceptability (all-cause discontinuations) at study endpoint.Of 25 RCTs, 19 studies tested second-generation LAIs (SGA-LAIs) and six first-generation LAIs (FGA-LAIs). Due to a disconnected network, FGA-LAIs were analyzed separately, with poor data quality. The SGA-LAIs network included 8,418 individuals (males=63%, mean age=39.3 years). All SGA-LAIs outperformed placebo in reducing acute symptoms at study endpoint (median follow-up=13 weeks). They were more acceptable than placebo with the only exception of olanzapine, for which no differences with placebo emerged. Additionally, we distinguished between different LAI formulations of the same antipsychotic to explore potential pharmacokinetic differences. Most formulations outperformed placebo in the very short-term (2 weeks or less), regardless of the need for initial oral supplementation.SGA-LAIs are evidence-based treatments in acutely ill individuals with schizophrenia-spectrum disorders. Findings support the use of SGA-LAIs to manage psychopathology and improve adherence right from the acute phases of illness.

Pharmacokinetic modeling of sulfamethoxazole-trimethoprim and sulfadiazine-trimethoprim combinations in broilers

Sulfonamides (S) are old bacteriostatic antibiotics which are widely prescribed in combination with trimethoprim (TMP) for the treatment of various diseases in food-producing animals such as poultry. Nowadays, the 1:5 dose ratio of TMP/S used in broilers is a direct transposition of the ratio determined in Human decades ago for TMP/sulfamethoxazole (SMX), aiming to obtain a supposed synergistic plasma concentration ratio of 1:19. However, major pharmacokinetics (PK) differences exist according to the sulfonamide used in the combination. Here, we generated new PK data in broilers after a cross-over design with IV and the oral administration of 2 major sulfonamides, sulfadiazine (SDZ) and SMX, in combination with TMP, and analyzed the data via a population pharmacokinetic (popPK) modeling approach. Results showed that TMP has a greater plasma to tissue distribution than both sulfonamides with a higher volume of distribution (0.51 L/kg for SDZ, 0.62 L/kg for SMX and 3.14 L/kg for TMP). SMX has the highest elimination half-life (2.83 h) followed by SDZ and TMP (2.01 h and 1.49 h, respectively). The oral bioavailability of the 3 molecules was approximately 100%. Bodyweight could explain some of the inter-individual variability in the volume of distribution of SDZ and SMX and the clearance of SDZ and TMP, as heavier broilers have higher typical values. Monte Carlo simulations of a large virtual broiler population (n = 1,000) showed that the targeted plasma ratio of TMP:S of 1:19 was rarely or never reached at the individual level for both combinations at the marketed doses and greatly varies over time and between individuals, questioning the relevance of the 1:5 dose ratio for current formulations of TMP/S.

Development and Application of a Physiologically Based Pharmacokinetic Model for Elagolix in the Adult and Adolescent Population.

Endometriosis, a common and distressing gynecological condition, affects fertility and causes pain, is often managed with medications such as Elagolix. The present study aimed to construct a physiologically based pharmacokinetic (PBPK) model for elagolix to predict its pharmacokinetics in different populations, including those with special conditions, to enhance treatment strategies for endometriosis. The PBPK model was optimized using observational data based on the oral administration of elagolix in a healthy Chinese population under fasting conditions. Model accuracy was further verified by comparing the predicted postprandial elagolix concentration data for healthy Chinese individuals with observed data and by comparing these values with the predicted values in a US population model with renal injury or following multiple-dose administration. Elagolix pharmacokinetic (PK) profiles in the Chinese and American populations exhibited no differences that were attributable to ethnicity. The model predicted in vivo PK in adolescents aged 14-18 years, revealing no clinically significant differences in the effects of elagolix between adolescents and adults. In addition, no predicted PK differences in individuals with overweight were observed. However, notable variations emerged in those classified as obesity class 2 and above compared to healthy individuals. Our study presents a novel PBPK model for elagolix in healthy Chinese women, addressing a clinical data gap for its use in adolescents and obese patients. By validating the model with real-world factors, including diet and renal impairment, we provide initial pharmacokinetic predictions for these populations, contributing to a more informed clinical approach.

Comparative study on pharmacokinetics of extract from Bufonis venenum and its liposomes

Bufadienolides and indolealkylamines, the primary active components in Bufonis venenum, have rapid clearance from the body with a short half-life, leading to low bioavailability. Moreover, Bufadienolides and indolealkylamines are associated with serious adverse effects. In order to reduce the toxicities, minimize the adverse effects and simultaneously load lipophilic bufadienolides and hydrophilic indolealkylamines with satisfactory drug loading and encapsulation rate, we prepared Bufonis venenum extract-liposomes (BVE-LP). To compare the pharmacokinetic differences between Bufonis venenum extract (BVE) and its liposomes, ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay was established to simultaneously detect the 12 chemical components in rat plasma. Results of pharmacokinetic study in SD rats showed that the highest exposure based on the area under the plasma concentration-time curve (AUC0-t) was obtained by 5-hydroxytryptamine with a mean value of 267.097 μg/L*h in BVE-LP group, which was 72.36 % higher as compared to that obtained in Bufonis venenum extract (BVE) group with a mean value of AUC0-t of 154.966 μg/L*h. The exposure (AUC0-t) of desacetylcinobufotalin, desacetylcinobufagin, arenobufagin and telocinobufagin in BVE-LP group was 111.89 %, 94.13 %, 134.08 %, and 92.94 % higher when compared to that in BVE group. With the employment of liposomes, there was an obvious decrease in the clearance of bufotenidine, desacetylcinobufotalin, gamabufotalin, arenobufagin, and telocinobufagin. The terminal half life (t1/2) of desacetylcinobufotalin, gamabufotalin, arenobufagin, and telocinobufagin in BVE-LP group was increased by 185.96 %, 292.64 %, 196.78 % and 131.29 % when compared to that in BVE group. All the results above indicated that a slower elimination rate and more exposure of some bufadienolides and indolealkylamines was obtained by BVE-LP when compared to BVE group, which verified BVE-LP could provide a therapeutic option for effective delivery of Bufonis venenum in clinical. Data availabilityThe data will be shared on reasonable request to the corresponding author.

SUBA-itraconazole in the treatment of systemic fungal infections.

Conventional itraconazole (c-ITZ) can be used for a variety of fungal infections although variable absorption has been a significant limitation. Super-bioavailable itraconazole (SUBA-ITZ) is a novel formulation that overcomes absorption concerns by utilizing a polymer-matrix to disperse active drug and facilitate dissolution. The pH-driven matrix allows concurrent protonpump inhibitor administration without significant effects on drug concentrations. The enhanced bioavailability of SUBA-ITZ allows for lower dosing, while achieving similar serum concentrations as c-ITZ and SUBA-ITZ is now USFDA approved in the treatment of blastomycosis, histoplasmosisand aspergillosis. Common side effects of SUBA-ITZ include gastrointestinal disorders, peripheral edemaand drug-induced hypertension. Given the significant differences in pharmacokinetics between the formulations, c-ITZ and SUBA-ITZ capsules are not considered interchangeable. It is important to note that drug errors may occur when transitioning a patient from one formulation to another.

Design, Optimization, and Characterization of Zolmitriptan Loaded Liposomal Gels for Intranasal delivery for acute migraine therapy

Zolmitriptan is the primary drug for the treatment of Migraine. However, the bioavailability of the drug is low and requires repetitive administration leading to side effects. Zolmitriptan's bioavailability can be improved by incorporating it into liposomes as a topical intranasal gel. The formulation was developed using a Central composite design employing a response surface approach. The new formulations were tested for particle size, shape, drug entrapment efficiency, and in vitro drug release. Permeation experiments and histopathology in rats were also conducted to determine the formulation's safety. The vesicle size was found to be in the range of 103.82±7.16 to 694.38±1.02 nm, zeta potential --19.28 to -32.8 mV, Entrapment Efficiency from 55.49±1.37 to 99.12±0.36 %, and cumulative drug release from 59.71±6.94 to 99.38±0.13 % respectively. In-vitro drug release of G1 and G3 gel formulations showed a non-Fickian released pattern during the studies. A comparison of the permeation coefficient of G1 (0.539 μg/cm2) and G3 (5.3 μg/cm2) showed a slight variation in the drug release rate after 24 hrs. For the liposomal gel and its solution, we found a significant difference in drug penetration of p0.05 after 12 hours compared to the control gel. There were substantial differences in bioavailability and pharmacokinetics between the optimal Liposomal Gel Formulation and other formulations, including the drug solution, liposomal suspension, and optimized formulation F12. The liposomal gel is non-irritating and safe for topical administration by histopathological investigations. Therefore, the study demonstrated that Zolmitriptan Liposomal gel has better efficacy, good tolerability, and enhanced bioavailability, making it an optimal treatment for acute Migraine.

Inter-Species Pharmacokinetic Modeling and Scaling for Drug Repurposing of Pyronaridine and Artesunate.

Even though several new targets (mostly viral infection) for drug repurposing of pyronaridine and artesunate have recently emerged in vitro and in vivo, inter-species pharmacokinetic (PK) data that can extend nonclinical efficacy to humans has not been reported over 30 years of usage. Since extrapolation of animal PK data to those of humans is essential to predict clinical outcomes for drug repurposing, this study aimed to investigate inter-species PK differences in three animal species (hamster, rat, and dog) and to support clinical translation of a fixed-dose combination of pyronaridine and artesunate. PK parameters (e.g., steady-state volume of distribution (Vss), clearance (CL), area under the concentration-time curve (AUC), mean residence time (MRT), etc.) of pyronaridine, artesunate, and dihydroartemisinin (an active metabolite of artesunate) were determined by non-compartmental analysis. In addition, one- or two-compartment PK modeling was performed to support inter-species scaling. The PK models appropriately described the blood concentrations of pyronaridine, artesunate, and dihydroartemisinin in all animal species, and the estimated PK parameters in three species were integrated for inter-species allometric scaling to predict human PKs. The simple allometric equation (Y = a × Wb) well explained the relationship between PK parameters and the actual body weight of animal species. The results from the study could be used as a basis for drug repurposing and support determining the effective dosage regimen for new indications based on in vitro/in vivo efficacy data and predicted human PKs in initial clinical trials.

Development and Quality Control of a Population Pharmacokinetic Model Library for Caspofungin.

Caspofungin is an echinocandin antifungal agent commonly used as the first-line therapy for invasive candidiasis, salvage therapy for invasive aspergillosis, and empirical therapy for presumed fungal infections. Pharmacokinetic (PK) variabilities and suboptimal exposure have been reported for caspofungin, increasing the risk of insufficient efficacy. This work aimed to develop a caspofungin population pharmacokinetic (popPK) library and demonstrate its utility by assessing the probability of target attainment across diverse settings. We established a caspofungin popPK model library following a rigorous literature review, re-implementing selected models in R with rxode2. Quality control procedures included a comparison of different studies and assessing covariate impacts. Model libraries were primarily used to perform Monte Carlo simulations to estimate target attainment and guide personalized dosing in Candida infections. A total of 13 models, one- or two-compartment models, were included. The most significant covariates were body size (weight and body surface area), liver function, and albumin level. The results show that children and adults showed considerable differences in pharmacokinetics. For C. albicans and C. parapsilosis, none of the populations achieved a PTA of ≥90% at their respective susceptible MIC values. In contrast, for C. glabrata, 70% of the adult studies reached a PTA of ≥90%, while all pediatric studies achieved the same PTA level. At the recommended dosage, adult patients showed notably lower exposure to caspofungin compared to pediatric patients. Considering body size, liver function, and serum albumin is crucial when determining caspofungin dosage regimens. Furthermore, further research is required to comprehensively understand the pharmacokinetics of caspofungin in pediatric patients.

Comparable efficacy of oral bendamustine versus intravenous administration in treating hematologic malignancies.

The purpose of this study was to analyze potential differences in antitumor efficacy and pharmacokinetics between intravenous (IV) bendamustine and a novel orally administered (PO) bendamustine agent that is utilizing the beneficial properties of superstaturated solid dispersions formulated in nanoparticles. Pharmacokinetics of IV versus PO bendamustine were determined by analysis of plasma samples collected from NSG mice treated with either IV or PO bendamustine. Plasma samples were analyzed using liquid chromatography-mass spectrometry following a liquid-liquid extraction to determine peak bendamustine concentration, area under the concentration-time curve, and the half-life in-vivo. In-vitro cytotoxicity of bendamustine against human non-Hodgkin Burkitt's Lymphoma (Raji), multiple myeloma (MM.1s), and B-cell acute lymphoblastic leukemia (RS4;11) cell lines was determined over time using MTS assays. Luciferase-tagged versions of the aforementioned cell lines were used to determine in-vivo bendamustine cytotoxicity of IV versus PO bendamustine at two different doses. Bendamustine at a high dose in-vitro causes cell death. There was no significant difference in antitumor activity between IV and novel PO bendamustine at a physiologically relevant concentration in all three xenograft models. In-vivo pharmacokinetics showed the oral bioavailability of bendamustine in mice to be 51.4%. The novel oral bendamustine agent tested exhibits good oral bioavailability and systemic exposure for in-vivo antitumor efficacy comparable to IV bendamustine. An oral bendamustine formulation offers exciting clinical potential as an additional method of administration for bendamustine and warrants further evaluation in clinical studies.

The Intoxication Equivalency of 11-Hydroxy-Δ9-Tetrahydrocannabinol Relative to Δ9-Tetrahydrocannabinol.

Δ9-Tetrahydrocannabinol (THC) is a psychoactive phytocannabinoid found in the Cannabis sativa plant. THC is primarily metabolized into 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC), which may themselves be psychoactive. There is very little research-based evidence concerning the pharmacokinetics and pharmacodynamics of 11-OH-THC as an individual compound. Male C57BL/6 mice were treated with THC or 11-OH-THC via intraperitoneal injection, tail vein intravenous injection, or oral gavage, and whole-blood compound levels were measured to determine pharmacokinetic parameters [Cmax, time to Cmax (Tmax), elimination half-life, area under the curve, apparent volume of distribution, systemic clearance, terminal rate constant, and absolute bioavailability] while also monitoring changes in catalepsy, body temperature, and nociception. 11-OH-THC achieved a Tmax at 30 minutes for all routes of administration. The maximum concentration at 30 minutes was not different between intravenous and intraperitoneal routes, but the oral gavage Cmax was significantly lower. THC had a 10-minute time to the maximum concentration, which was the first blood collection time point, for intravenous and intraperitoneal and 60 minutes for oral gavage, with a lower Cmax for intraperitoneal and oral gavage compared with intravenous. When accounting for circulating compound levels and ED50 responses, these data suggest that 11-OH-THC was 153% as active as THC in the tail-flick test of nociception and 78% as active as THC for catalepsy. Therefore, 11-OH-THC displayed equal or greater activity than the parent compound THC, even when accounting for pharmacokinetic differences. Thus, the THC metabolite 11-OH-THC likely plays a critical role in the bioactivity of cannabis; understanding its activity when administered directly will aid in the interpretation of future animal and human studies. SIGNIFICANCE STATEMENT: This study establishes that the primary metabolite of THC, 11-OH-THC, displays equal or greater activity than THC in a mouse model of cannabinoid activity when directly administered and even when accounting for route of administration, sex, pharmacokinetic, and pharmacodynamic differences. These data provide critical insight into the bioactivity of THC metabolites that will inform the interpretation of future in vivo cannabinoid research and represent a model for how THC consumption and metabolism may affect cannabis use in humans.

Simulating Healthy Participant Pharmacokinetics for Renal and Hepatic Impairment Studies: Retrospective Assessment of the Approach

The recruitment of a parallel, healthy participants (HPs) arm in renal and hepatic impairment (RI and HI) studies is a common strategy to assess differences in pharmacokinetics. Limitations in this approach include the underpowered estimate of exposure differences and the use of the drug in a population for which there is no benefit. Recently, a method was published by Purohit et. al. (2023) that leveraged prior population pharmacokinetic (PopPK) modeling-based simulation to infer the distribution of exposure ratios between the RI/HI arms and HPs. The approach was successful, but it was a single example with a robust model having several iterations of development and fitting to extensive HP data. To test in more studies and models at different stages of development, our catalogue of RI/HI studies was searched, and those with suitable properties and from programs with available models were analyzed with the simulation approach. There were 9 studies included in the analysis. Most studies were associated with models that would have been available at the time (ATT) of the study, and all had a current, final model. For 3 studies, the HP PK was not predicted well by the ATT (2) or final (1) models. In comparison to conventional analysis of variance (ANOVA), the simulation approach provided similar point estimates and confidence intervals of exposure ratios. This PopPK based approach can be considered as a method of choice in situations where the simulation of HP data would not be an extrapolation, and when no other complicating factors are present.Graphical

A phase 1 study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD), and to determine the recommended phase 2 dose (RP2D) of subcutaneous (SC) cetrelimab (CET) in patients (pts) with advanced solid malignancies.

e14602 Background: In part (P) 1 and P2 of LUC1001 (NCT02908906), the RP2D of intravenous (IV) CET was established as 240 mg IV once every 2 weeks (Q2W) or 480 mg IV Q4W, and the PK/PD characteristics, safety profile, and clinical activity were consistent with known and approved PD-1 inhibitors (Felip et al. Cancer Chemother Pharmacol 2022). CET administered SC was investigated in P3 and P4 of LUC1001. Methods: In P3 and P4 of LUC1001, safety, PK, PD, and clinical activity of low- (30 mg/mL [CET-LC]) and high- (150 mg/mL [CET-HC]) concentration SC CET formulations, respectively, were evaluated. Key entry criteria were advanced or refractory solid tumors, previous receipt of or ineligibility for standard treatment, and being anti-PD-1/PD-L1/2–naïve. In P3, SC CET-LC injection was administered at a dose level of 600 mg with a 6-week dosing interval between doses 1 and 2, then Q3W dosing after dose 2. In P4, SC CET-HC injection was administered as a single loading dose of 900 mg, followed by 600 mg Q3W. Results: Among 30 enrolled pts (P3: n = 11; P4: n = 19), median age was 54.5 years; 17 (57%) were male; most (29 [97%]) were White and heavily pretreated, with a median of 3 (range, 1-8) prior lines of therapy. Most common tumor types were colorectal cancer (6 [20%]), breast cancer (4 [13%]), cholangiocarcinoma and NSCLC (3 [10%] each). Most commonly reported adverse events (AE) were fatigue (11 [37%]), ALT increased (7 [23%]), abdominal pain, constipation and AST increased (6 [20%] each). Overall, 20 (67%) pts had CET-related AEs, 1 (3%) of which led to CET discontinuation. Eight (27%) pts had ≥1 CET-related ≥Grade 3 AE. Immune-related AEs were reported in 9 (30%) pts. No pts experienced systemic-administration–related reactions, and 2 (6%) pts experienced Grade 1 administration-site reactions. No CET-related serious AEs were reported. Durable responses were observed in 2 (7%) patients (cholangiocarcinoma in P3 and thymoma in P4). Stable disease ≥24 weeks was observed in 4 (13% [P3, 0 (0%); P4, 4 (21%)]) pts. According to PK data, the 900-mg SC CET loading dose followed by 600-mg SC CET Q3W would likely result in comparable exposure as observed at steady state with IV RP2Ds. No differences in PK, including absorption, were observed between CET-LC and CET-HC formulations. Maximum PD-1 receptor occupancy was achieved, consistent with historical IV and SC data. Incidence of anti-CET antibodies (P3, 3/11 [27%]; P4, 0/13 [0%]) was low, and no neutralizing antibodies (0/24 [0%]) were detected. Conclusions: SC CET demonstrated a safety profile similar to IV CET. Based on safety, PK, and PD data, the RP2D of SC CET was established as a loading dose of 900 mg followed by 600 mg Q3W. Studies are planned to further evaluate the safety and efficacy of SC CET in combination with other agents. Clinical trial information: NCT02908906 .

Population pharmacokinetic, pharmacodynamic and efficacy modeling of SB12 (proposed eculizumab biosimilar) and reference eculizumab

PurposeTo describe, compare similarity of pharmacokinetic (PK), pharmacodynamic (PD) and efficacy of SB12 and reference eculizumab (ECU) and find clinically significant covariate relationships.MethodsThe PK, PD (terminal complement activity) and efficacy (LDH) data of SB12 and ECU were obtained from 289 subjects from phase I and phase III studies. One- and two-compartment PK models with first-order elimination were evaluated for SB12 and ECU. For PD and efficacy, both direct and indirect models were tested. The impact of covariates on PK, PD and efficacy parameters was assessed. Relationship between PK/PD and PD/efficacy was characterized. This modeling was performed using NONMEM version 7.4 (Icon Development Solutions, Ellicott City, MD, USA).ResultsThe two-compartment model adequately described the PK of SB12 and ECU, and the subject’s weight was chosen as a clinically significant covariate affecting drugs’ clearance and central volume of distribution. Treatment group was not a significant covariate affecting clearance. The direct response model using inhibitory sigmoid Emax and sigmoid Emax relationship well described the PK/PD relationship and PD/efficacy relationship of SB12 and ECU, respectively. Through this modeling, the relationships between PK, PD and efficacy were characterized. There were no differences in PK, PD and efficacy parameters between SB12 and ECU in pooled populations of healthy subjects and paroxysmal nocturnal haemoglobinuria (PNH) patients.ConclusionThe population modeling showed PK, PD and efficacy similarities between SB12 and ECU in pooled population of healthy subjects and PNH patients, supporting the totality of evidence on biosimilarity for SB12.

Sex-specific considerations in cardiovascular drug therapy.

Despite major advances in cardiac research over the past three decades, cardiovascular disease (CVD) still remains the leading cause of morbidity and mortality in women and men worldwide. However, a major challenge for health care providers is that the current guidelines for cardiovascular drug therapies do not consider the impact of sex in the development of treatment plan for optimizing therapies for women. Clinical research in recent years suggests significant pharmacological and pharmacokinetic differences between females and males, which have been attributed in part to differences in body composition, plasma protein binding capacity, drug metabolism, and excretion. Herein, we provide a comprehensive review regarding sex-specific differences and drugs commonly used for CVDs in women and men. Understanding how sex-related differences influence drug efficacy and CVD outcomes is crucial for not only optimizing treatment strategies for women and men but also to encourage the implementation of specific guidelines that address sex difference as a consideration for the treatment of CVDs.

Italian Association of Hospital Cardiologists Position Paper 'Gender discrepancy: time to implement gender-based clinical management'.

It has been well assessed that women have been widely under-represented in cardiovascular clinical trials. Moreover, a significant discrepancy in pharmacological and interventional strategies has been reported. Therefore, poor outcomes and more significant mortality have been shown in many diseases. Pharmacokinetic and pharmacodynamic differences in drug metabolism have also been described so that effectiveness could be different according to sex. However, awareness about the gender gap remains too scarce. Consequently, gender-specific guidelines are lacking, and the need for a sex-specific approach has become more evident in the last few years. This paper aims to evaluate different therapeutic approaches to managing the most common women's diseases.