Steady-state Volume Of Distribution Research Articles

Research Note: Pharmacokinetics of bromhexine hydrochloride in broilers after single oral and intravenous administration

The current study aimed to investigate the pharmacokinetics of bromhexine hydrochloride in broilers after single intravenous (IV) and oral (PO) administration at 2.5 mg/kg body weight (BW). The trial adopted a randomized, parallel-controlled design, where 20 twelve-wk-old broilers were randomly assigned to either the PO or IV group. Blood samples were collected at predetermined time points, and plasma was further separated for analysis. The bromhexine hydrochloride concentrations in plasma samples were determined using an ultra-performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-MS/MS) method. Noncompartmental analysis (NCA) using Phoenix software was conducted to analyze the concentration versus time data of bromhexine hydrochloride in every chicken. Subsequently, the main pharmacokinetic parameters between the 2 groups were statistically analyzed using SPSS software. Results from NCA revealed that after oral administration at 2.5 mg/kg BW, bromhexine hydrochloride exhibited slow absorption, reaching an average peak concentration of 32.72 ng/mL at 1.78 h. However, incomplete absorption was observed, with an absolute bioavailability of only 20.06% ± 10.84%. Additionally, bromhexine hydrochloride displayed wide distribution, with a steady-state distribution volume (VSS) of 22.55 ± 13.45 L/kg, and slow elimination, with a clearance (Cl) of 1.52 ± 0.38 L/h/kg. Furthermore, gender effects were assessed on the pharmacokinetics of bromhexine hydrochloride in broilers, revealing better absorption in male broilers compared to females. This disparity may be attributed to the faster blood flow and richer blood volume typically found in male broilers.

Pharmacokinetics of intravenous piperacillin/tazobactam among patients with peritoneal dialysis-associated peritonitis.

Currently, pharmacokinetic information on intravenous (IV) piperacillin/tazobactam in patients with peritoneal dialysis-associated peritonitis (PD peritonitis) is limited. This study employed a prospective single-dose pharmacokinetic design to assess the pharmacokinetics of IV piperacillin/tazobactam in these patients. Four patients with PD peritonitis who received an IV loading dose of 4000 mg/500 mg piperacillin/tazobactam were enrolled in this study. The concentrations of piperacillin and tazobactam in plasma, peritoneal dialysis fluid (PDF) and urine were determined by high-performance liquid chromatography. Non-compartmental methods were used for pharmacokinetic analysis. During a 6-h dwell time for chronic ambulatory peritoneal dialysis (CAPD), 9.23 ± 4.01% of the piperacillin was recovered in the PDF. This result is greater than that observed in patients without peritonitis in prior research. Piperacillin's PD clearance (CLPD), steady-state volume of distribution (Vss) and terminal half-life (t 1/2) were 5.79 ± 2.55 mL/min, 24.35 ± 11.26 L and 5.74 ± 1.53 h, respectively. These values are also higher than those of patients without peritonitis in a prior study. Eight hours following the loading dosage, the plasma and PDF piperacillin concentrations of all patients (98.25 ± 26.03 and 52.70 ± 22.99 mg/L, respectively) surpassed the Pseudomonas aeruginosa and Enterobacterales Clinical and Laboratory Standards Institute susceptible breakpoints. In summary, the CLPD, Vss and t 1/2 for piperacillin were found to be greater in patients with PD peritonitis than in CAPD patients without peritonitis when compared with the results of a previous study. The IV loading dose of 4000 mg/500 mg piperacillin/tazobactam is sufficient to treat peritonitis caused by susceptible P. aeruginosa and Enterobacterales. The multiple-dose pharmacokinetics of IV piperacillin and tazobactam in this specific patient group should be further investigated.

Pharmacokinetics and Immunogenicity of Abbv-383, a B-Cell Maturation Antigen (BCMA) × CD3 Bispecific T-Cell-Redirecting Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction ABBV-383 is a fully human, silenced Fc region IgG4 monoclonal, BCMA × CD3 T-cell-engaging bispecific antibody with 2 BCMA-binding domains and a low-affinity CD3-binding domain. ABBV-383 has shown promising activity following intravenous (IV) infusion every three weeks (Q3W) as monotherapy in patients (pts) with RRMM in an ongoing phase 1 study (D'Souza A, et al. J Clin Oncol. 2022 Nov 1;40(31):3576-3586; Voorhees et al. Blood 2022;140[suppl 1]:4401). Herein, preliminary pharmacokinetic (PK) and immunogenicity results from Q3W regimens of this study and impact of soluble BCMA (sBCMA) on ABBV-383 PK are reported. Methods In the phase 1 study (NCT03933735), adult pts with RRMM, who were previously exposed to ≥3 prior multiple myeloma agents including ≥1 proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody, received Q3W IV infusion at doses 0.025 - 120 mg in escalation (ESC) phase, and at 20 mg, 40 mg, and 60 mg in expansion (EXP) phase. Serial blood samples for PK characterization were collected in cycles 1, 3, and 6 along with sparse/periodic samples throughout the study. Blood samples were also collected throughout the study to detect anti-drug antibodies (ADAs) for immunogenicity characterization and to determine sBCMA concentrations. Appropriate validated assays were used to determine ‘total’ (unbound and bound to sBCMA) and ‘free’ (unbound and partially bound to sBCMA) ABBV-383 serum concentrations, to detect/determine ADAs/titers, and to determine total sBCMA concentrations. ‘Total’ and ‘free’ ABBV-383 serum concentrations from cycles 1, 3, and 6 were used to calculate individual PK parameters (peak concentration [C max], trough concentration [C trough], area under the concentration-time curve [AUC], terminal phase elimination half-life [t 1/2], clearance [CL], and steady state volume of distribution [V ss]) using non-compartmental analysis in Phoenix WinNonlin Version 8.2. Immunogenicity was summarized using ADA/titer data. Impact of baseline/pre-dose sBCMA concentrations on ‘total’ and ‘free’ ABBV-383 PK parameters from cycles 1, 3, and 6 was explored. Results ‘Total’ and ‘free’ ABBV-383 intensive PK data (cycles 1, 3, and 6) were available from 169 and 157 pts, respectively, representing Q3W regimens in ESC and EXP cohorts and ADA data were available from 186 evaluable subjects. Preliminary PK results suggest that ‘total’ and ‘free’ ABBV-383 exhibited approximately dose-proportional PK between 5.4-120 mg Q3W. Estimated t 1/2 for ‘total’ and ‘free’ ABBV-383 ranged between 11-12 days and 8-11 days, respectively, with steady state achieved by cycle 4 in Q3W EXP cohorts. Estimated CL and V ss were consistent with those of a typical IgG4 antibody in humans. Across EXP Q3W regimens, accumulation (cycle 3 vs. cycle 1) was 30%-60% in C max and 60%-177% in C trough for ‘free’ and ‘total’ ABBV-383. ABBV-383 exposures (AUC tau and C trough) of ‘total’ ABBV-383 were 28-74% higher than those representing ‘free’ ABBV-383 among the EXP Q3W regimens with no/minimal observed differences in C max (≤21%). Higher sBCMA levels prior to treatment appeared to reduce ‘free’ ABBV-383 PK exposures with pronounced reduction at lower doses (e.g., 20 mg) and in cycle 1, however the effect diminished in later cycles (cycles 3 and 5). Preliminary assessment of immunogenicity indicated an ADA incidence of 3.8% (7/186) with low titers ranging between 11.7 and 187 titer units and no impact on PK. Conclusions ABBV-383 exhibited a PK profile with relatively long half-life and low incidence of immunogenicity. Overall, sBCMA impacted (reduced) the ‘free’ ABBV-383 (pharmacologically active component) PK exposures only, with pronounced effect at lower doses and the effect is consistent with understanding of treatment dependent sBCMA dynamics over time. Determination of both ‘total’ and ‘free’ ABBV-383 serum concentrations allowed to demonstrate such underlying impact of sBCMA on PK.

Disposition kinetics of tildipirosin in alpacas after parenteral administrations

Tildipirosin is a macrolide antibiotic marketed in veterinary medicine to treat respiratory infections in pigs and calves. There are no pharmacokinetics studies of tildipirosin after parenteral administration in alpacas which is an extremely decisive step for determining dosage regimen. Thus, the aim of the present study was to establish the disposition fate of tildipirosin following intravenous (IV), intramuscular (IM) and subcutaneous (SC) administrations in alpacas. A crossover study was used, and each alpaca received a single dose of tildipirosin by IV and IM or SC. All the routes of administration were adequately tolerated, and no adverse reactions was observed in any alpaca. Tildipirosin in alpacas reached peak concentrations (Cmax = 0.68 µg/mL vs. 0.79 µg/mL) at 0.22 and 0.50 h (tmax) after IM and SC administration, respectively, with an absolute bioavailability of >100 % for both routes of administration. Steady-state volume of distribution and clearance were 6.02 ± 1.34 L/kg and 2.76 ± 0.28 L/h/kg, respectively. Tildipirosin presents a particular pharmacokinetic behaviour in alpacas, distinctive from other ruminant species, confirming the need to perform studies in the target species in order to promote rational dose regimens of this antimicrobial to maximize its efficacy, minimize its toxicity and avoid the emergence of resistant bacteria.

In vitro and in vivo pharmacokinetic characterization, chiral conversion and PBPK scaling towards human PK simulation of S-MRI-1867, a drug candidate for Hermansky-Pudlak syndrome pulmonary fibrosis

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that affects lysosome-related organelles, often leading to fatal pulmonary fibrosis (PF). The search for a treatment for HPS pulmonary fibrosis (HPSPF) is ongoing. S-MRI-1867, a dual cannabinoid receptor 1 (CB1R)/inducible nitric oxide synthase (iNOS) inhibitor, has shown great promise for the treatment of several fibrotic diseases, including HPSPF. In this study, we investigated the in vitro ADME characteristics of S-MRI-1867, as well as its pharmacokinetic (PK) properties in mice, rats, dogs, and monkeys. S-MRI-1867 showed low aqueous solubility (< 1 µg/mL), high plasma protein binding (>99%), and moderate to high metabolic stability. In its preclinical PK studies, S-MRI-1867 exhibited moderate to low plasma clearance (CLp) and high steady-state volume of distribution (Vdss) across all species. Despite the low solubility and P-gp efflux, S-MRI-1867 showed great permeability and metabolic stability leading to a moderate bioavailability (21-60%) across mouse, rat, dog, and monkey. Since the R form of MRI-1867 is CB1R-inactive, we investigated the potential conversion of S-MRI-1867 to R-MRI-1867 in mice and found that the chiral conversion was negligible. Furthermore, we developed and validated a PBPK model that adequately fits the PK profiles of S-MRI-1867 in mice, rats, dogs, and monkeys using various dosing regimens. We employed this PBPK model to simulate the human PK profiles of S-MRI-1867, enabling us to inform human dose selection and support the advancement of this promising drug candidate in the treatment of HPSPF.

Evaluation of plasma and urine pharmacokinetics of tranexamic acid for equine medication control.

This study aimed to evaluate the pharmacokinetics (PK) of tranexamic acid (TXA) in horses and estimate its irrelevant plasma and urine concentrations using the pharmacokinetic/pharmacodynamic (PK/PD) approach by applying the Pierre-Louis Toutain model. TXA was intravenously administered to eight thoroughbred mares, and plasma and urine TXA concentrations were quantified by liquid chromatography/tandem mass spectrometry. The quantified data were used to calculate the PK parameters of TXA in horses. The plasma elimination curves were best-fitted to a three-compartment model. Using the Toutain model approach, irrelevant plasma and urine TXA concentrations were estimated to be 0.0206 and 0.997 μg/mL, respectively. The typical values of clearance, steady-state volume of distribution, and steady-state urine-to-plasma ratio were 0.080 L/kg/h, 0.86 L/kg, and 49.0, respectively. The obtained irrelevant concentrations will be useful for establishing relevant regulatory screening limits for effective control of TXA use in horse racing and equestrian sports.

The Absolute Bioavailability and Absorption, Metabolism, and Excretion of Ipatasertib, a Potent and Highly Selective Protein Kinase B (Akt) Inhibitor.

Ipatasertib (GDC-0068) is a potent, highly selective, small-molecule inhibitor of protein kinase B (Akt) being developed by Genentech/Roche as a single agent and in combination with other therapies for the treatment of cancers. To fully understand the absorption, metabolism, and excretion of ipatasertib in humans, an open-label study using 14C-radiolabeled ipatasertib was completed to characterize the absolute bioavailability (period 1) and mass balance and metabolite profiling (period 2). In period 1, subjects were administered a 200 mg oral dose of ipatasertib followed by an 80 μg (800 nCi) intravenous dose of [14C]-ipatasertib. In period 2, subjects received a single oral dose containing approximately 200 mg (100 μCi) [14C]-ipatasertib. In an integrated analytical strategy, accelerator mass spectrometry was applied to measure the 14C microtracer intravenous pharmacokinetics in period 1 and fully profile plasma radioactivity in period 2. The systemic plasma clearance and steady-state volume of distribution were 98.8 L/h and 2530 L, respectively. The terminal half-lives after oral and intravenous administrations were similar (26.7 and 27.4 hours, respectively) and absolute bioavailability of ipatasertib was 34.0%. After a single oral dose of [14C]-ipatasertib, 88.3% of the administered radioactivity was recovered with approximately 69.0% and 19.3% in feces and urine, respectively. Radioactivity in feces and urine was predominantly metabolites with 24.4% and 8.26% of dose as unchanged parent, respectively; indicating that ipatasertib had been extensively absorbed and hepatic metabolism was the major route of clearance. The major metabolic pathway was N-dealkylation mediated by CYP3A, and minor pathways were oxidative by cytochromes P450 and aldehyde oxidase. SIGNIFICANCE STATEMENT: The study provided definitive information regarding the absolute bioavailability and the absorption, metabolism, and excretion pathways of ipatasertib, a potent, novel, and highly selective small-molecule inhibitor of protein kinase B (Akt). An ultrasensitive radioactive counting method, accelerator mass spectrometry was successfully applied for 14C-microtracer absolute bioavailability determination and plasma metabolite profiling.

Failure to predict amikacin elimination in critically ill patients with cancer based on the estimated glomerular filtration rate: applying PBPK approach in a therapeutic drug monitoring study.

The aim of this work was to integrate the Therapeutic Drug Monitoring (TDM) with the model-informed precision dosing (MIPD) approach, using Physiologically-based Pharmacokinetic/Pharmacodynamic (PBPK/PD) modelling and simulation, to explore the relationship between amikacin exposure and estimated glomerular filtration rate (GFR) in critically ill patients with cancer. In the TDM study, samples from 51 critically-ill patients with cancer treated with amikacin were analysed. Patients were stratified according to renal function based on GFR status. A full-body PBPK model with 12 organs model was developed using Simcyp V. 21, including steady-state volume of distribution of 0.21 L/kg and renal clearance of 6.9 L/h in healthy adults. PK parameters evaluated were within the 2-fold error range. During the validation step, predicted vs observed amikacin clearance values after single infusion dose in patients with normal renal function, mild and moderate renal impairment were 7.6 vs 8.1 L/h (7.5mg/kg dose); 3.8 vs 4.5 L/h (1500mg dose) and 2.2 vs 3.1 L/h (25mg/kg dose), respectively. However, predicted vs observed amikacin clearance after a single dose infusion of 1400mg in critically-ill patients with cancer were 1.46 vs 1.63 (P = 0.6406) L/h (severe), 2.83 vs 1.08 (P < 0.05) L/h (moderate), 4.23 vs 2.49 (P = 0.0625) L/h (mild) and 7.41 vs 3.36 (P < 0.05) L/h (normal renal function). This study demonstrated that estimated GFR did not predict amikacin elimination in critically-ill patients with cancer. Further studies are necessary to find amikacin PK covariates to optimize the pharmacotherapy in this population. Therefore, TDM of amikacin is imperative in cancer patients.

Pharmacokinetics of the novel 5-HT4 receptor agonist, DA-6886, in dogs

The pharmacokinetics of a new 5-hydroxytryptamine receptor 4 agonist, DA-6886, intended for the treatment of constipation-predominant irritable bowel syndrome, were evaluated in beagle dogs following both intravenous and oral administration of DA-6886 (1–10 mg/kg). The study also examined the effects of gender and food on the pharmacokinetics of DA-6886 in dogs. DA-6886 demonstrated dose-proportional area under the plasma concentration–time curve (AUC) values and dose-independent clearance (21.0–24.6 mL/min/kg) after administration via both routes. The steady-state volume of distribution (V ss) for DA-6886 was dose-independent and relatively large (6.76–8.57 L/kg), aligning with its observed high distribution in rat tissues. No significant differences were observed in the pharmacokinetics of DA-6886 between male and female dogs. Post oral administration, extent of absolute oral bioavailability (BA) was relatively high (48.2–96.1%) in contrast to the rates observed in rats (18.9–55.0%). Dogs that were fed exhibited a significantly lower C max and a delayed T max in comparison to those that were fasted. However, the AUC values were similar between the two groups. The extended stomach transit time in the fed state may account for this delayed absorption of DA-6886 without substantial changes in AUC.

Physiologically based pharmacokinetic (PBPK) model that describes enhanced FcRn-dependent distribution of monoclonal antibodies (mAbs) by pI-engineering in mice

We previously reported that monoclonal antibodies (mAbs) with a high isoelectric point (pI) value tended to exhibit fast plasma clearance (CL) and large steady-state volume of distribution (Vdss) in mice. However, the positive correlation between pI, CL, and Vdss cannot be described by the reported physiologically based pharmacokinetic (PBPK) models, in which FcRn-mediated transcytosis of mAbs is set to be minimal compared to convection-mediated transport. To address this issue, physiological parameters (lymph flow rate, reflection coefficient, endothelial uptake clearance, and FcRn concentration) were optimized based on the pharmacokinetic profiles of mAbs with various pI values in wild type and FcRn-deficient (beta-2-microglobulin knockout [KO]) mice. Simulations using the PBPK model developed in this study showed a positive correlation between pI, CL and Vdss observed in wild-type mice. Therefore, this model successfully characterized our hypothetical mechanism that an electrostatic positive interaction between mAbs and the endothelial membrane enhances FcRn-mediated transcytosis of mAbs, resulting in large Vdss. We sought to determine the right contribution of the two pathways of antibody distribution to the interstitial space and established a new model that could effectively capture the effect of pI on FcRn-mediated distribution of mAbs in the body.

Pharmacokinetics and oral bioavailability of cannabidiol in horses after intravenous and oral administration with oil and micellar formulations.

Intravenous pharmacokinetics and oral bioavailability of cannabidiol (CBD) with different formulations have not been investigated in horses and may represent a starting point for clinical studies. To describe pharmacokinetics after intravenous and oral administrations with oil and micellar formulations and simulate different treatments. Single intravenous experiment and two-way randomised oral experiments, Latin-square design. Eight healthy horses received intravenous CBD at 1.00 mg/kg dose, oral CBD in sesame oil and in micellar formulation, both at 10.00 mg/kg. Concentrations were measured using LC-MS/MS and fitted by nonlinear mixed effect modelling. Parameters obtained were used to simulate single and multiple treatments at steady state. Intravenous and oral concentrations were simultaneously fitted using a three-compartment model. Final estimates indicate that CBD has a volume of distribution of 36 L/kg associated with a systemic clearance of 1.46 L/h/kg and half-lives ranged between 24 and 34 h. Oral bioavailability was close to 14% for both oral administrations. Simulated dose regimen of CBD every 12 and 24 h predicted similar percentages to reach effective plasma concentration with both oral formulation at 10.00 mg/kg. A small horse population was used (8 horses per trial). Oral bioavailability was low at the doses studied but fell within the range described for horse and other species. CBD had a high steady-state volume of distribution, a high clearance and long half-lives. No adverse reactions were detected at any dose or route. The micellar formulation showed a faster absorption and higher concentration peak, while the oil formulation presented lower levels, but more maintained over time. Simulations predicted that both could be useful in multiple oral dose treatments. These results indicated that CBD could be of interest, but further studies are needed to evaluate its clinical use in horses.

How effective are ionization state-based QSPKR models at predicting pharmacokinetic parameters in humans?

Optimizing the pharmacokinetics (PK) of a drug candidate to support oral dosing is a key challenge in drug development. PK parameters are usually estimated from the concentration-time profile following intravenous administration; however, traditional methods are time-consuming and expensive. In recent years, quantitative structure-pharmacokinetic relationship (QSPKR), an in silico tool that aims to develop a mathematical relationship between the structure of a molecule and its PK properties, has emerged as a useful alternative to experimental testing. Due to the complex nature of the various processes involved in dictating the fate of a drug, the development of adequate QSPKR models that can be used in real-world pre-screening situations has proved challenging. Given the crucial role played by a molecule's ionization state in determining its PK properties, this work aims to build predictive QSPKR models for PK parameters in humans using an ionization state-based strategy. We divide a high-quality dataset into clusters based on ionization state at physiological pH and build global and ion subset-based 'local' models for three major PK parameters: plasma clearance (CL), steady-state volume of distribution (VDss), and half-life (t1/2). We use a robust methodology developed in our lab entitled 'EigenValue ANalySis' that accounts for the stereospecificity in drug disposition and use the support vector machine algorithm for model building. Our findings suggest that categorizing compounds in accordance with ionization state does not result in improved QSPKR models. The narrow ranges in the endpoints along with redundancies in the data adversely affect the ion subset-based QSPKR models. We suggest alternative approaches such as elimination route-based models that account for drug-transporter interactions for CL and chemotype-specific QSPKR for VDss.

Exploring the Past to Inform the Future to Optimize the Pharmacokinetics of Vancomycin in Children With Severe Burn Injuries.

Sepsis remains one of the leading causes of death among pediatric patients with burn injuries. Despite limited vancomycin pharmacokinetic (PK) information within this population, it is widely used to treat severe burn injuries. Those with severe burns are at risk of nephrotoxicity, with an incidence of acute kidney injury (AKI) over 50%. Delivering an effective vancomycin dose and avoiding unnecessary toxicity is essential for improved patient outcomes. This was a retrospective analysis of 115 children aged 0.2 months to 18 years with severe burns, >10% total body surface area. Vancomycin was given via intravenous infusion; blood samples were drawn between 6- and 12-hour postinfusion. A population pharmacokinetic model was developed using nonlinear mixed-effect modeling (Monolix, version 2016R1). A one-compartment model described a steady-state volume of distribution (V), dependent on weight. Vancomycin clearance (CL) was influenced by age and estimated creatinine clearance (CrCL). The study population's (median age = 4 years, median weight = 20 kg, median total body surface area (%TBSA) = 40%) median V and CL were calculated to be 1.25 L/kg (95% CI, 1.04-1.46) and 0.15 L/h/kg (95% CI, 0.126-0.165), respectively. The PK model was explicitly developed to characterize the impact of physiological changes in children under 18 years of age and the percentage of the burn surface area using limited data. The analysis determined that weight, age, and estimated CrCL were important covariates in predicting vancomycin PK with high variability in CL and V.

Population Pharmacokinetics and Exposure-Response Analyses for Risankizumab in Patients with Active Psoriatic Arthritis.

IntroductionRisankizumab is an anti-IL23 monoclonal antibody approved for the treatment of moderate to severe plaque psoriasis and active psoriatic arthritis (PsA). This work characterizes the pharmacokinetics of risankizumab in PsA compared with psoriasis and evaluates the efficacy and safety exposure–response relationships in PsA.MethodsThe population pharmacokinetic analyses included data from 1527 participants that originated from one phase 1 healthy participant study, one phase 2 dose-ranging study in patients with PsA with an open-label extension study, and two pivotal phase 3 studies in patients with PsA, where the clinical regimen of risankizumab 150 mg administered subcutaneously (SC) at weeks 0, 4, and every 12 weeks thereafter was compared with placebo. Pharmacokinetics were analyzed using nonlinear mixed-effects modeling. Simulation analyses using the final model were conducted to evaluate the impact of covariates on exposure. Data from 1407 patients with PsA from the phase 3 studies were included in the exposure–response analyses. Graphical analyses were used to evaluate efficacy and safety exposure–response relationships, and logistic regression was conducted for further assessment of efficacy exposure–response relationships.ResultsRisankizumab pharmacokinetics were well described by a two-compartment model with first-order SC absorption and elimination. None of the evaluated covariates showed clinically relevant impact on exposure. On the basis of the final model, systemic clearance, steady-state volume of distribution, and terminal phase elimination half-life were estimated to be ~ 0.31 L/day, 11.1 L, and 26.3 days, respectively, for a typical 90 kg patient with PsA. Absolute SC bioavailability was estimated to be 83.5%. Exposure–response quartile analyses suggested that exposures associated with the clinical regimen maximized efficacy across the endpoints evaluated. No exposure dependency was observed for key safety endpoints.ConclusionsRisankizumab exhibited linear and time-independent pharmacokinetics in patients with PsA and was comparable to patients with plaque psoriasis. Efficacy and safety exposure–response analyses support that the clinical regimen achieved robust efficacy with a favorable safety profile for patients with active PsA.Clinical Trials: NCT02596217, NCT02719171, NCT02986373, NCT03671148, and NCT03675308.Clinical Trials: NCT02596217, NCT02719171, NCT02986373, NCT03671148, and NCT03675308.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00495-0.

Nonclinical Pharmacokinetic Evaluation of Desidustat: a Novel Prolyl Hydroxylase Inhibitor for the Treatment of Anemia.

Desidustat is a novel prolyl hydroxylase domain(PHD) inhibitor for the treatment of anemia. The objective of this study was to investigate the pharmacokinetics and drug-drug interaction properties of desidustat using invitro and invivo nonclinical models. Invitro, Caco2 cell permeability, plasma protein binding, metabolism, cytochrome P450 (CYP) inhibition, and CYP induction were examined. In vivo, pharmacokinetic studies of oral bioavailability in mice, rats, dogs and monkeys, dose linearity, tissue distribution, and excretion in rats were conducted. In Caco-2 cells, the apparent permeability of desidustat was high at low pH and low at neutral pH. The oral bioavailability (%F) of desidustat was 43-100% with a mediantime to reach peak concentration (Tmax)of about 0.25-1.3h across species. Desidustat displayed a low mean plasma clearance (CL) of 1.3-4.1mL/min/kg (approximately 1.8-7.4% of hepatic blood flow), and the mean steady-state volume of distribution (Vss) was 0.2-0.4L/kg (approximately 30-61% of the total body water). Desidustat showed a dose-dependent increase in exposures over the 15-100mg/kg dose range. It was rapidly distributed in various tissues, with the highest tissue-to-blood ratio in the liver (1.8) and kidney (1.7). Desidustat showed high plasma protein binding and was metabolically stable in human liver microsomes, hepatocytes, and recombinant CYPs. It did not show significant inhibition of major drug-metabolizing CYP enzymes (IC50>300µM) or the potential to induce CYP1A2 and CYP3A4/5 (up to 100µM) in HepG2 cells. It may have minimal potential of clinical drug-drug interaction when used in combination with iron supplements or phosphate binders. Desidustat was primarily excreted unchanged in urine (25% of the oral dose) and bile (25% of the oral dose) in rats. The mean elimination half-life of desidustat ranged from 1.0 to 5.3h and 1.3 to 5.7h across species after intravenous and oral administration, respectively. Taken together, desidustat is well absorbed orally. It showed a dose-dependent increase in exposure, did not accumulate in tissue, and was eliminated via dual routes. It is metabolically stable, has minimal potential to cause clinical drug-drug interactions (DDIs), and demonstrates discriminable pharmacokinetic properties for the treatment of anemia.

Pharmacokinetics of tildipirosin in horses after intravenous and intramuscular administration and its potential muscle damage

Tildipirosin is a novel semisynthetic macrolide antibiotic exclusively used in veterinary practice to treat respiratory infections. There are no pharmacokinetic or safety information available regarding the use of tildipirosin after intramuscular administration in horses. Thus, the objective of this work was to determine the disposition kinetics of tildipirosin after intravenous (IV) and intramuscular (IM) administration in horses and its potential muscle damage and cardiotoxicity. Six mature, Spanish-breed horses were used in a crossover study with a washout period of 30 days. Tildipirosin (18%) was administered at single doses by IV (2 mg/kg) and IM (4 mg/kg) routes. Tildipirosin plasma concentrations were determined by HPLC assay with ultraviolet detection. Muscle damage and inflammation were assessed by creatine kinase (CK) and haptoglobin (Hp), respectively. Creatine kinase myocardial band (CK-MB) and troponin (Tn) were used to evaluate cardiotoxicity. Tildipirosin in horses reached peak concentrations (Cmax = 1.13 μg/mL) at 0.60 h (tmax) after IM administration with an absolute bioavailability of 109.2%. Steady-state volume of distribution and clearance were 3.31 ± 0.57 L/kg and 0.22 ± 0.02 L/h/kg, respectively. Tildipirosin did not cause cardiotoxicity since CK-MB and Tn basal levels were not significantly different from those obtained after several days post-administration. Mild local reactions were observed after IM administration. This local inflammation was associated with mild myolysis (CK 239–837 UI/L), which was detectable for 48 h. In brief, tildipirosin could help to treat respiratory infections in horses because it showed extensive distribution, high bioavailability and did not provoke general adverse reactions.

Basic Aspects and the Overview on Pharmacokinetics and Studies on Drug Distribution- A Panoramic Review

Patients who are in critical condition display a variety of organ dysfunctions and frequently need to be treated with a range of medications, such as sedatives, analgesics, neuromuscular blockers, antibiotics, inotropes, and gastric acid suppressants. A crucial component of treatment for this patient population is comprehending how organ dysfunction might change the pharmacokinetics of medications. Due to gastrointestinal failure, many medications will need to be administered intravenously. When the oral route is an option, hypomotility, changes in gut pH, and enteral feeding may affect bioavailability. The main factors affecting medication clearance, and consequently steady-state drug concentrations, efficacy, and toxicity in a given patient, are hepatic and renal dysfunction. Many medications are cleared from the body primarily through oxidative metabolism, and it is becoming increasingly understood how important it is for critically ill patients to have diminished hepatic cytochrome P450 system activity. Both filtration and secretion clearance pathways are necessary for the elimination of parent medications and their active metabolites, making renal failure equally crucial. Renal failure is frequently a secondary cause of changes in the steady-state volume of distribution, which can lower the body's effective medication concentrations. Failure of the endocrine, endothelium, muscular, or central neurological systems may also have an impact on how a medication is metabolized. For some medications, there is strong evidence that changes in pharmacokinetic characteristics depend on time. To maximize the pharmacodynamic response and result, it is essential to understand the underlying pathophysiology in the critically sick and utilize pharmacokinetic principles in the selection of drug and dosing regimen.

The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Abrocitinib, a Selective Janus Kinase Inhibitor, in Humans.

Abrocitinib is an oral once-daily Janus kinase 1 selective inhibitor being developed for the treatment of moderate-to-severe atopic dermatitis. This study examined the disposition of abrocitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite (M) profiles. The results indicated abrocitinib had a systemic clearance of 64.2 L/h, a steady-state volume of distribution of 100 L, extent of absorption >90%, time to maximum plasma concentration of ∼0.5 hours, and absolute oral bioavailability of 60%. The half-life of both abrocitinib and total radioactivity was similar, with no indication of metabolite accumulation. Abrocitinib was the main circulating drug species in plasma (∼26%), with 3 major monohydroxylated metabolites (M1, M2, and M4) at >10%. Oxidative metabolism was the primary route of elimination for abrocitinib, with the greatest disposition of radioactivity shown in the urine (∼85%). In vitro phenotyping indicated abrocitinib cytochrome P450 fraction of metabolism assignments of 0.53 for CYP2C19, 0.30 for CYP2C9, 0.11 for CYP3A4, and ∼0.06 for CYP2B6. The principal systemic metabolites M1, M2, and M4 were primarily cleared renally. Abrocitinib, M1, and M2 showed pharmacology with similar Janus kinase 1 selectivity, whereas M4 was inactive. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of abrocitinib, a Janus kinase inhibitor for atopic dermatitis, in humans, as well as characterization of clearance pathways and pharmacokinetics of abrocitinib and its metabolites.

Predicting Antibiotic Effect of Vancomycin Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation: Dense Sampling versus Sparse Sampling.

This study aimed to investigate the effect of a structural pharmacokinetic (PK) model with fewer compartments developed following sparse sampling on the PK parameter estimation and the probability of target attainment (PTA) prediction of vancomycin. Two- and three-compartment PK models of vancomycin were used for the virtual concentration–time profile simulation. Datasets with reduced blood sampling times were generated to support a model with a lesser number of compartments. Monte Carlo simulation was conducted to evaluate the PTA. For the two-compartment PK profile, the total clearance (CL) of the reduced one-compartment model showed a relative bias (RBias) and relative root mean square error (RRMSE) over 90%. For the three-compartment PK profile, the CL of the reduced one-compartment model represented the largest RBias and RRMSE, while the steady-state volume of distribution of the reduced two-compartment model represented the largest absolute RBias and RRMSE. A lesser number of compartments corresponded to a lower predicted area under the concentration–time curve of vancomycin. The estimated PK parameters and predicted PK/PD index from models built with sparse sampling designs that cannot support the PK profile can be significantly inaccurate and unprecise. This might lead to the misprediction of the PTA and selection of improper dosage regimens when clinicians prescribe antibiotics.

189P Pharmacokinetics (PK) of sacituzumab govitecan (SG) in patients (Pts) with metastatic triple-negative breast cancer (mTNBC) and other solid tumors

SG is a novel antibody-drug conjugate (ADC) composed of an anti–Trop-2 antibody coupled to SN-38 via a proprietary, hydrolyzable linker. SG is approved for pts with mTNBC who received ≥2 prior chemotherapies (>1 in the metastatic setting) and has accelerated approval for pts with metastatic urothelial cancer who received prior platinum-containing chemotherapy and a PD-1/PD-L1 inhibitor. These analyses evaluated the PK of SG, Free SN-38, and Total Antibody (tAB) with SG administration. Population PK (PopPK) models were developed using data from 529 pts across 2 clinical studies, IMMU-132-01 (phase 1/2 in pts with advanced epithelial cancers including TNBC, UC, and lung cancer; PK n=276) and ASCENT (phase 3 in pts with mTNBC who received ≥2 prior therapies (>1 in the metastatic setting); PK n=253). Pts received SG at 8 to 18 mg/kg IV (IMMU-132-01) or 10 mg/kg IV (ASCENT) on d1 and d8, of every 21d cycle. Clinically relevant covariates were evaluated to assess their impact on exposure. The PopPK models of SG and tAB were developed independently. The model of Free SN-38 was developed in a sequential manner with a first-order release of Free SN-38 (payload) from SG (the ADC). The typical parameter estimates for clearance and steady-state volume of distribution were 0.133 L/hr and 3.68 L for SG and 0.0164 L/hr and 4.26 L for tAB. Bodyweight correlated with the clearance and volume parameters of all 3 analytes, but with limited impact on the exposure with the clinical regimen. There was no model-predicted accumulation of either SG or Free SN-38 with repeated dosing. Overall, mild to moderate renal impairment, mild hepatic impairment, age, sex, baseline albumin level, race, ECOG status, tumor type, UGT1A1 genotype or Trop-2 expression did not have a clinically relevant impact on exposure of any of the evaluated analytes. The PK of SG, Free SN-38, and Total Antibody were well characterized based on a robust dataset across two large trials. The analyses supported the approved 10 mg/kg clinical regimen and did not identify a need for dose-adjustment based on any of the evaluated patient demographics or disease characteristics.