PK Simulation Research Articles

The Impact of Dexamethasone and Prednisone on Apixaban and Rivaroxaban Exposure in COVID-19 Patients: A Physiologically Based Pharmacokinetic Modeling Study.

Dexamethasone (DEX) is currently the treatment of choice for patients with oxygen-dependent COVID-19. It has been observed, primarily in vitro, that dexamethasone induces the expression of CYP3A and the ABCB1 gene, which encodes P-glycoprotein (P-gp). This has raised concerns about potential interactions between DEX and substrates of CYP3A and P-gp, such as direct oral anticoagulants (DOAC). Currently, there is limited robust evidence to support a clinically significant interaction between DEX and DOAC. Using physiologically based pharmacokinetic modeling (PBPK), we investigated the impact of DEX administered in the context of SARS-CoV-2 infection on the pharmacokinetics of apixaban (APX) and rivaroxaban (RVX). After validating the induction effect of the DEX compound on two CYP3A4 substrates using the limited available studies, we optimized the compound in a COVID-19 patient population, where significantly higher DEX plasma concentrations were observed compared to healthy volunteers. Our PBPK-based PK simulations showed a 20% decrease in the AUC of APX and RVX in a worst-case scenario and when DEX was administered at 6 mg PO for 10 days. This finding confirms the limited clinical data currently available and supports the use of APX and RVX with DEX in COVID-19 patients at low-risk for thrombo-embolism. In addition, our results suggest that prednisone (PRED), when used at an equipotent dose, could serve as a viable alternative to DEX, given its less pronounced induction effect on APX and RVX. Further research is needed to validate these findings and to explore the clinical implications of using PRED in place of DEX in such scenarios.

Establishment of an Integrated Population Pharmacokinetic/Pharmacodynamics Model of Apixaban in Chinese Healthy Population Adjusting for Key Genetic Variants.

To improve the understanding of pharmacokinetic/pharmacodynamic (PK/PD) profiles of apixaban, supporting personalised drug prescriptions for future patients. Genetic as well as nongenetic factors can affect the predictable PK and PD characteristics of apixaban. Establish a integrated popPK/PD model that adjusts for critical genetic variant. The integrated PK/PD models was characterized on the basis of PK (apixaban blood concentration) and PD (prothrombin time (PT), activated partial thromboplastin time (APTT), and anti-FXa activity) data from 181 healthy Chinese volunteers. Other investigated covariate variables included: Meaningful intrinsic and extraneous determinants, correlated markers (ABCG2, F13A1, C3, etc.). A total of 2877 PK concentration observations were included in the modeling dataset. The PK model of apixaban is adopted by single compartment model with first-order oral absorption. The estimated values of total clearance rate (CL/F), apparent distribution volume (V/F), and absorption rate constant (KA) in the final model are 3.37 l/h, 28.2 l, and 0.781 l/h, respectively. The PK model includes significance covariates such as FOOD, RBC, WT, and gene (ABCG2). The PD model of apixaban is adopted by a linear direct effect model with additive error, which was used to describe the relationship between markers such as APTT, PT, anti-FXa, versus plasma concentration. PK simulation within the modelled dose range is similar to clinical real date, while PD simulation results also show that the simulated exposure parameters is within the range of the literature. We established a comprehensive PK/PD model and used it to simulate markers level such as APTT, PT, and anti-FXa of apixaban. Individual predictive values with a dose of 2.5 mg are basically within the expected recommended range.

Brivaracetam exposure-response predictions in pediatric patients from age 1 month: Extrapolation of levetiracetam adult-pediatric scaling to brivaracetam

BackgroundAn adult population pharmacokinetic/pharmacodynamic (PK/PD) model for the antiseizure medication (ASM) brivaracetam (BRV) was previously extended to children aged 4–16 years by using a pediatric BRV population PK model. Effects were scaled using information from a combined adult-pediatric PK/PD model of a related ASM, levetiracetam (LEV). ObjectiveTo scale an existing adult population PK/PD model for BRV to children aged 1 month to < 4 years using information from a combined adult-pediatric PK/PD model for LEV, and to predict the effective dose of BRV in children aged 1 month to < 4 years using the adult BRV PK/PD model modified for the basal seizure rate in children. Material and methodsAn existing adult population PK/PD model for BRV was scaled to children aged from 1 month to < 4 years using information from a combined adult-pediatric PK/PD model for LEV, an ASM binding to the same target protein as BRV. An existing adult-pediatric PK/PD model for LEV was extended using data from UCB study N01009 (NCT00175890) to include children as young as 1 month of age. The BRV population PK model was updated with data up to 180 days after first administration from BRV pediatric studies N01263 (NCT00422422) and N01266 (NCT01364597). PK and PD simulations for BRV were performed for a range of mg/kg doses to predict BRV effect in pediatric participants, and to provide dosing recommendations. ResultsThe extended adult-pediatric LEV PK/PD model was able to describe the adult and pediatric data using the same PD model parameters in adults and children and supported the extension of the adult BRV PK/PD model to pediatric patients aged 1 month to < 4 years. Simulations predicted exposures similar to adults receiving BRV 100 mg twice daily (b.i.d.), when using 3 mg/kg b.i.d. for weight < 10 kg, 2.5 mg/kg b.i.d. for weight ≥ 10 kg and < 20 kg, and 2 mg/kg b.i.d. for weight ≥ 20 kg in children aged 1 month to < 4 years. PK/PD simulations show that maximum BRV response is expected to occur with 2–3 mg/kg b.i.d. dosing of BRV in children aged 1 month to < 4 years, with an effective dose of 1 mg/kg b.i.d. for some participants. ConclusionDevelopment of an adult-pediatric BRV PK/PD model allowed characterization of the exposure-response relationship of BRV in children aged 1 to < 4 years, providing a maximal dose allowance based on weight.

P765 A Novel Monoclonal Antibody Drug Candidate SPY001 Targeting Integrin ɑ4β7 for the Treatment of IBD Demonstrates Prolonged Half-Life in Non-Human Primates

Abstract Background Background: Antagonism of the interaction between the cellular adhesion integrin ɑ4β7 and endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) has proven to be relatively safe and effective in the treatment for Crohn’s disease (CD) and ulcerative colitis (UC). Additional benefit may be gained from an ɑ4β7 antagonist given via the subcutaneous (SC) route at extended intervals (eg, every 8 to 12 weeks) during maintenance therapy. Methods The humanized monoclonal IgG1 antibody SPY001 binds to the same ɑ4β7 epitope as vedolizumab and includes a YTE modification within the Fc region to increase its serum half-life via increased affinity for the neonatal Fc receptor (FcRn), thereby favoring recycling into the circulation over degradation. Half-life extension was evaluated via pharmacokinetic analysis in Tg276 transgenic mice (hemizygous for human FcRn) following a single intravenous bolus dose of SPY001 (10 mg/kg, 5 mg/kg, 1 mg/kg) and in cynomolgus monkeys following a single bolus dose of SPY001 (150 mg/kg), given by either intravenous (IV) and subcutaneous (SC) administration. PK simulations in humans were based on allometric scaling of SPY001 clearance observed in cynomolgus monkey and conducted in MATLAB. Results In Tg276 mice, the half-life of SPY001 was 10-11 days across all dose cohorts compared to approximately 3 days for vedolizumab. In cynomolgus monkeys, the half-life of SPY001 was 19-23 days following a single IV or SC infusion, a significant increase over the reported half-life of 10 days for vedolizumab in cynomolgus monkeys. Based on allometric scaling of the clearance of SPY001 observed in this study, predictive simulations of SPY001 PK in humans suggested that Q8W-Q12W SC dosing at 300 mg would be able to achieve a C6-wks, induction ≥ 35 mg/mL and Ctrough, ss ≥ 6 mg/mL for simulated patients covering a large range of body weights and albumin concentrations. Conclusion SPY001 is a novel humanized monoclonal IgG1 with an extended half-life over that of vedolizumab in Tg276 mice and cynomolgus monkeys. It offers the potential for effective and safe treatment of CD and UC with the advantage of infrequent SC dosing. Further preclinical and clinical studies are warranted to demonstrate this potential.

Population Pharmacokinetic/Pharmacodynamic Models for P2Y12 Inhibitors: A Systematic Review and Clinical Appraisal Using Exposure Simulation.

Recent research indicates a correlation between plasma concentration of P2Y12 inhibitors and clinical events, particularly bleeding, which significantly impeded their clinical therapeutic performance. It is therefore vital to delve into the factors that might affect the plasma concentration. The study aims to summarize population pharmacokinetics/pharmacodynamics (PopPKPD) models for commonly prescribed P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) and assess bleeding risk in specific individual groups. The PopPKPD models of P2Y12 inhibitors were collected and summarized based on predetermined inclusion and exclusion criteria. The collected models were replicated in simulations, which were used to assess factors affecting plasma concentrations of P2Y12 inhibitors. Simulation results for special populations were compared to therapeutic window based on reported exposure-effect relationships (PK/PD-related bleeding and thrombotic clinical outcomes) to predict bleeding risk in special populations with different dosing regimens and cumulative covariates. Finally, 12 studies were included for PK simulation, 7 of which that also included PD data were subjected to further analysis, with the majority being based on Phase I or II trials. Simulations showed that several covariates such as female gender, weight, elderly can significantly impact on exposure, with special populations reaching up to 179% of the general population. However, after dose adjustment, blood concentrations for special populations can reach approximately ±20% of general population exposure. Therefore, lowering the maintenance dose of ticagrelor from 90 to 60 mg bid was first recommended to reduce bleeding risk without significantly increasing ischemic risk, particularly in elderly, small-weight Asian females. Lowering the maintenance dose of ticagrelor from 90 to 60 mg bid effectively reduces bleeding risk without increasing thrombotic infarction risk in elderly, small-weight Asian females.

Comparative Pharmacokinetic Studies of One‐Month Donepezil IM Depot and Once Daily Oral Tablet in Healthy Male Volunteers

AbstractBackgroundThis study is to evaluate the safety and tolerability of single dose of one‐month donepezil IM depot (GB‐5001) in healthy male volunteers and to compare pharmacokinetic parameters of 70mg donepezil IM depot and 10mg once daily oral tablet (Aricept®) in human.MethodIn this phase 1, a randomized, double‐blind, placebo‐controlled, dose‐escalation study, 48 healthy subjects were randomized to single dose of Aricept tablet or placebo or GB‐5001 (70mg or 140mg or 280mg) for 64 days. In this study, safety and tolerability of 70mg donepezil IM depot were examined by monitoring adverse events and vital signs. PK parameters such as AUCt, AUCinf, Cmax and Tmax were compared by measuring donepezil concentration after a single dose of 70mg IM depot and 10mg oral tablet.ResultA single dose of 70mg donepezil IM depot showed no significant adverse events and was well tolerated in healthy male volunteers. In 70mg GB‐5001, all the subjects had measurable concentrations up to 1512 h post dose. The geometric mean of PK exposure parameters are 6482.82 h*ng/mL, 6604.01 h*ng/mL and 11.40 ng/mL for AUCt(0‐1512h), AUCinf, and Cmax, respectively. The median peak concentration (Tmax) was observed at 432h post dose. In 10mg oral Aricept, all the subjects had measurable concentrations up to 240 h post dose. The geometric mean of PK exposure parameters are 656.84 h*ng/mL, 751.34 h*ng/mL and 17.68 ng/mL for AUCt(0‐240h), AUCinf, and Cmax, respectively. The median peak concentration (Tmax) was observed at 2.25 h post dose.ConclusionA single dose of 70mg donepezil IM depot was found to be safe and well tolerated in healthy male volunteers. The pharmacokinetic results of 70mg donepezil IM depot showed stable donepezil blood concentration for more than one month without burst drug release, and showed comparable unit dose drug exposure not lower than that of once daily 10mg oral formulation. Through the PK results for additional higher doses and multiple PK simulations, optimal once monthly dose of donepezil IM depot could be suggested which will be bioequivalent to 10mg once daily tablet.

Mechanistic Pharmacokinetics and Pharmacodynamics of GalNAc-siRNA: Translational Model Involving Competitive Receptor-Mediated Disposition and RISC-Dependent Gene Silencing Applied to Givosiran

Triantennary N-acetyl-D galactosamine (GalNAc)3-conjugated small interfering RNA (siRNA) have majorly advanced the development of RNA-based therapeutics. Chemically stabilized GalNAc-siRNAs exhibit extensive albeit capacity-limited (nonlinear) distribution into hepatocytes with additional complexities in intracellular liver disposition and pharmacology. A mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model of GalNAc-siRNA was developed to i) quantitate ASGPR-mediated disposition and downstream RNA-induced silencing complex (RISC)-dependent pharmacology following intravenous (IV) and subcutaneous (SC) dosing, ii) assess the kinetics of formed active metabolite, iii) leverage, as an example, published experimental data for givosiran, and iv) demonstrate PK translation across two preclinical species (rat and monkey) with subsequent prediction of human plasma PK. The structural model is based on competition between parent and formed active metabolite for occupancy and uptake via ASGPR into hepatocytes, intracellular sequestration and degradation, and downstream engagement of RNA-induced silencing complex (RISC) governing target mRNA degradation. The model jointly and accurately captured available concentration-time profiles of givosiran and/or AS(N-1)3′ givosiran in rat and/or monkey plasma, liver, and/or kidney following givosiran administered both IV and SC. RISC-dependent gene silencing of ALAS1 mRNA was well-characterized. The model estimated an in vivo affinity (KD) value of 27.7 nM for GalNAc-ASGPR and weight-based allometric exponents of −0.27 and −0.24 for SC absorption and intracellular (endolysosomal) degradation rate constants. The model well-predicted reported givosiran plasma PK profiles in humans. PK simulations revealed net-shifts in liver-to-kidney distribution ratios with increasing IV and SC dose. Importantly, decreases in the relative liver uptake efficiency were demonstrated following IV and, to a lesser extent, following SC dosing explained by differential ASGPR occupancy profiles over time.

Single dose tocilizumab for COVID-19 associated cytokine storm syndrome: Less is more.

We aim to evaluate the clinical pharmacokinetics of a single dose interleukin-6 (IL-6) antibody tocilizumab (TCZ) in methylprednisolone (MP)-treated COVID-19 patients with cytokine storm syndrome (CSS). MP pre-treated patients with COVID-19-associated CSS, defined as at least two elevations of C-reactive protein (CRP) >100 mg/L, ferritin >900 μg/L or D-dimers >1500 μg/L, received intravenous TCZ (8mg/kg, max. 800 mg) upon clinical deterioration. A nonlinear-mixed effects model was developed based on TCZ serum concentrations and dosing information. Population pharmacokinetic parameters were estimated and concentration-time profiles were plotted against individual predicted values. Fixed dose simulations were subsequently performed based on the final model. In total 40 patients (mean [SD] age: 62 [12] years, 20% female, body weight: 87 [17] kg) with COVID-19 induced CSS were evaluated on pharmacokinetics and laboratory parameters. A biphasic elimination of TCZ serum concentration was described by a homogeneous population pharmacokinetic model. Serum TCZ concentrations above the 1μg/L target saturation threshold were covered for 16 days in all evaluated patients treated with a single dose of 8mg/kg. In a simulation with TCZ 400 mg fixed dose, this condition of full IL-6 receptor occupancy at minimum serum concentration was also met. A single dose (8mg/kg, max. 800 mg) is sufficient to cover a period of 16 days of IL-6-mediated hyperinflammation in COVID-19-induced CSS in MP-treated patients. Based on body weight PK simulations, a fixed-dose tocilizumab of 400 mg should be considered to prevent overtreatment, future drug shortage and unnecessary drug expenditure.

623. Preliminary Dosing for Adolescent Hematopoietic Stem-Cell Transplant (HSCT) Recipients Based on Pharmacokinetic (PK), Safety, and Efficacy Data of Letermovir (LET) for Cytomegalovirus (CMV) Prophylaxis

Abstract Background LET is a CMV terminase complex inhibitor approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic HSCT recipients. Objectives of this ongoing study are to evaluate PK, safety, and efficacy of LET for CMV prophylaxis in adolescent allogeneic HSCT recipients (aged 12 to &amp;lt; 18 years). Methods This is a Phase 2b nonrandomized, multicenter, open-label, sequential dose escalation study (NCT03940586). Participants (pts) were divided into 3 age groups, the oldest (AG1) comprising adolescents. AG1 pts received the recommended adult 480 mg LET dose (240 mg with cyclosporine A [CsA]) once-daily orally (PO) or intravenously (IV). Pediatric target exposures were based on model-predicted Phase 3 population PK simulations for adult HSCT recipients: 16,900 h.ng/mL (480 mg PO without [w/o] CsA) to 147,800 h.ng/mL (480 mg IV w/o CsA). PK parameters were determined by non-compartmental analysis for 14/28 AG1 pts. Results All 28 AG1 pts enrolled were CMV-seropositive (median age: 13.5 [range, 12–17] years; median weight: 53.8 [range, 28.7–95.0] kg; White: 53.6%). PK (N=14): Of 13 evaluable AG1 pts (weight, 30.4–87.7 kg), 8 received 480 mg LET alone (oral/IV; Table 1); 6/8 achieved exposures within the target range and 2/8 (oral, n=1; IV, n=1) achieved exposures above the target range but below the maximum observed in the development program. 5 AG1 pts received 240 mg LET (oral/IV) with CsA; 5/5 achieved exposures within the target range. Safety (N=28): No major safety concerns were reported for AG1 pts receiving LET, similar to the adult LET safety profile. Efficacy (N=25): The proportion of AG1 pts receiving LET with clinically significant CMV infection (CMV disease/pre-emptive treatment for CMV viremia) through week 24 post-HSCT was similar (24%) to that for adults receiving LET in the pivotal Phase 3 study (37.5%). Conclusion Administration of adult LET doses for CMV prophylaxis post-HSCT in this adolescent cohort resulted in exposures within the development program safety margins, and was associated with similar efficacy and safety to LET use in adult patients. Preliminary results support 480 mg (240 mg with CsA) as an oral and IV LET dose in adolescent HSCT recipients, with a final dose recommendation after study completion. Disclosures Andreas H. Groll, MD, Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp &amp; Dohme, and Pfizer: Advisor/Consultant|Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp &amp; Dohme, and Pfizer: Served at the speakers’ bureau|Gilead Sciences, Merck Sharp &amp; Dohme, and Pfizer: Grant/Research Support Johannes H. Schulte, MD, German Cancer Consortium (DKTK): Support by Ali Bulent Antmen, MD, PhD, Novo Nordisk, Pfizer, Roche, Takeda: Advisor/Consultant Valerie L. Teal, MS, Merck &amp; Co., Inc.: Stocks/Bonds|Merck Sharp &amp; Dohme LLC: Current or former employee Barbara A. Haber, MD, Merck &amp; Co., Inc.: Stocks/Bonds|Merck Sharp &amp; Dohme LLC: Current or former employee Luzelena Caro, PhD, Merck &amp; Co., Inc.: Stocks/Bonds|Merck Sharp &amp; Dohme LLC: Current or former employee Jacqueline B. McCrea, PharmD, Merck &amp; Co., Inc.: Stocks/Bonds|Merck Sharp &amp; Dohme LLC: Current or former employee Craig Fancourt, PhD, Merck &amp; Co., Inc.: Stocks/Bonds|Merck Sharp &amp; Dohme LLC: Current or former employee Karsten Menzel, PhD, Merck &amp; Co., Inc.: Stocks/Bonds|Merck Sharp &amp; Dohme LLC: Current or former employee Cyrus Badshah, MD, PhD, Merck &amp; Co., Inc.: Stocks/Bonds|Merck Sharp &amp; Dohme LLC: Current or former employee.

Pharmacodynamics Assessment of Aducanumab in 5XFAD mice: A MODEL‐AD PTC Study

AbstractBackgroundThe Preclinical Testing Core (PTC) of the Model Organism Development for Evaluation of Late Onset Alzheimer’s Disease (MODEL‐AD) consortium established a rigorous preclinical drug testing strategy with go/no‐go decision points that permits unbiased assessments of therapeutic agents. As part of the pipeline validation, the chimeric murinized therapeutic antibody aducanumab (chAducanumab), was selected for evaluation in 5XFAD mice.MethodsInitial PK modeling and simulation was guided by literature and Aβ reductions from a pilot cohort of 9 month aged 5XFAD mice following 1x/week treatment of 30 mg/kg chAducanumab for 4 weeks. These pilot data were used to inform the chronic dosing regimen for the PD study which started at an age in 5XFAD mice where significant amyloid plaque accumulation was present (9 mos). PD endpoints (n=10‐12/sex/genotype/treatment) were assessed at the conclusion of chronic treatment, and included: 18‐FDG and 18F‐AV45 PET/CT, autoradiography, immunohistochemistry, AB40 and AB42 in plasma and brain fractions, and a behavioral battery. An additional cohort was enrolled for comprehensive cognitive testing using touchscreen learning and pattern separation tasks and evaluated for electroencephalography (EEG) activity using wireless telemetry.ResultsPK/PD modeling revealed slow clearance of chAducanumab following IP dosing with a T1/2 of ∼2.5 days. Therefore, the dose regimen for chronic PD studies included 0.1, 1.56, and 30 mg/kg administered 1x weekly for 12 weeks. Treatment with chAducanumab resulted in dose‐ and sex‐dependent reduction in amyloid deposition via 18F‐AV45 PET. Glucose uptake via 18F‐FDG PET similarly showed a dose dependent reversal of glycolytic loss in key brain regions. Cognitive assessments indicated no effect on learning however an improvement in pattern separation was observed with chAducanumab in females but not males. EEG analysis revealed improvements in delta, alpha, and beta oscillations with chAducanumab treatment. Multi‐omics analysis are in progress.ConclusionschAducanumab treatment in 5XFAD mice resulted in the expected reductions in brain amyloid consistent with clinical findings. Moreover, chAducanumab showed a unique glycolytic restoration profile in 5XFAD mice and improvements in some aspects of cognitive function. Together these data positively support pipeline validation of the MODEL‐AD PTC for evaluating therapeutic antibodies.

Subcutaneous Dose Selection of Lecanemab for Treatment of Subjects with Early Alzheimer’s Disease (EAD)

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils. Lecanemab 10 mg/kg IV biweekly dose (10BW) is being evaluated in the Clarity AD Phase 3 study in Early AD. A Phase 1 study was conducted to assess the absolute bioavailability (BA) of subcutaneous (SC) administration relative to IV infusion. Modeling and simulation analysis was conducted to demonstrate equivalence of a fixed weekly SC dose to body weight‐based IV 10BW dose with regard to lecanemab exposure, safety and efficacy.MethodBased on estimates of BA and absorption rate constant from Phase 1 and the population PK model describing lecanemab PK after IV infusion, estimates of the area under the concentration‐time curve (AUC) and maximum concentration (Cmax) at steady‐state were generated for the proposed fixed SC dose and IV 10BW. Exposure‐response simulations were conducted to compare positron emission tomography (PET) standard uptake ratio (SUVr)as a measure of pharmacodynamic effect, and incidence of amyloid related imaging abnormality‐E (ARIA‐E) as a measure of safety between SC and IV doses. The impact of body weight on the lecanemab exposure, reduction in amyloid PET SUVr and ARIA‐E risk when administered as a fixed SC dose and body weight‐based IV dose were explored.ResultPhase 1 data support a proposed fixed lecanemab SC dose of 720 mg administered weekly (720W). PK simulations demonstrate that the AUC of SC 720W were similar to IV 10BW. Exposure‐response simulations demonstrate comparable reduction in amyloid PET SUVr following SC 720W and IV 10BW, and lower incidence of ARIA‐E in SC 720W due to lower Cmax following SC administration. Lecanemab exposure differences between a fixed SC dose and body weight‐based IV dose were observed at the extremes of body weight; however, this did not have a meaningful effect on the reduction in PET SUVr and ARIA‐E risk.ConclusionThis analysis demonstrates that the proposed SC 720W results in equivalent AUC predicted to attain a comparable reduction in amyloid PET SUVr and a lower Cmax predicted to produce a lower incidence of ARIA‐E compared to IV 10BW.

Defining Exposure Predictors of Meropenem That Are Associated with Improved Survival for Severe Bacterial Infection: A Preclinical PK/PD Study in Sepsis Rat Model.

Background: The pharmacokinetic/pharmacodynamic (PK/PD) index of carbapenems that best correlates with in vivo antimicrobial activity is percent time of dosing interval in which free drug concentration remains above MIC (%fT &gt; MIC), while the magnitudes of the PK/PD index of carbapenems remains undefined in critically ill sepsis patients. Methods: A sepsis rat model was first developed by comparing the survival outcomes after intraperitoneal injection of different inoculum size (1-10 × 107 CFU) of Pseudomonas aeruginosa ATCC9027 (MIC = 0.125 mg/L) in neutropenic rats. The PK characteristics of the model drug meropenem in the developed sepsis rat model was then evaluated, and PK modeling and simulation was applied to design meropenem dosing regimens attaining various PD targets (40%fT &gt; MIC, 100%fT &gt; MIC, and 100%fT &gt; 4 × MIC). The microbiological response and survival outcomes for different meropenem treatment regimens were investigated in the rat sepsis model (n = 12 for each group). Results: The optimal inoculum for the rat sepsis model was 1 × 107 CFU of Pseudomonas aeruginosa ATCC9027. A one-compartment model with first-order absorption best described the PK of meropenem in sepsis rats. Pronounced survival prolongation and lower hazard risk were observed in the treatment groups of 50 or 75 mg/kg/q2.4h (100%fT &gt; MIC) and 75 mg/kg/q2h (100%fT &gt; 4 × MIC) compared to the 75 mg/kg/q6h (40%fT &gt; MIC) group, while meropenem groups with PD targets of 100%fT &gt; MIC and 100%fT &gt; 4 × MIC showed comparable survival curves. Microbiological response for different PD targets is inconclusive due to irregular bacterial counts in blood samples. Conclusions: The PD target of 40%fT &gt; MIC is suboptimal for sepsis rats, and the aggressive 100%fT &gt; 4 × MIC target does not provide a survival benefit against the target of 100%fT &gt; MIC.

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

C-Terminal Lysine Processing of IgG in Human Suction Blister Fluid: Implications for Subcutaneous Administration.

C-terminal lysine (CTK) is often classified as a potential critical quality attribute for therapeutic antibodies being developed for subcutaneous (SC) administration because of its potential to impact antibody SC bioavailability/pharmacokinetics (PK). This classification both inflates development costs and increases comparability risks for SC administration of antibodies. However, prior risk assessments of CTK have not fully considered biotransformation of CTK in the SC space, which may play an important role given that circulating carboxypeptidases in humans rapidly process CTK on intravenously administered antibodies. Here, CTK biotransformation in biofluid derived from human SC space was investigated. The representative fluid from the human SC space was sampled from 10 healthy human subjects using the suction blister method. Glycosylated antibody containing high levels of CTK (expressed using a carboxypeptidase D CRISPR/Cas9 knockout CHO cell line) was incubated in the collected suction blister fluids (SBFs), recovered using cognate antigen pulldowns, and characterized for remaining CTK levels using intact and reduced liquid chromatography-mass spectrometry (LC-MS) analysis. CTK processing (i.e., carboxypeptidase activity) was evident in all SBF and exhibited first-order kinetics with rate constants of 2.18 ± 0.57 d-1 (at 37 °C). PK simulations that integrated CTK processing pathways and their associated rate constants were subsequently performed using a range of clinically observed PK parameters for therapeutic antibodies, including atezolizumab- and pertuzumab-specific parameters. The impact of CTK content (even up to 100%) on SC PK outcomes such as bioavailability and Ctrough were modest (<14%) for all combinations of PK parameters tested in the sensitivity analysis. This study forms the cornerstone data package for derisking CTK as a PK liability for antibody SC programs and highlights the usefulness of fully considering biotransformation during product quality criticality assessments.

Altered intravenous drug disposition in people living with cystic fibrosis: A meta‐analysis integrating top‐down and bottom‐up data

Cystic fibrosis (CF) has been linked to altered drug disposition in various studies. However, the magnitude of these changes, influencing factors, and underlying mechanisms remain a matter of debate. The primary aim of this work was therefore to quantify changes in drug disposition (top‐down) and the pathophysiological parameters known to affect pharmacokinetics (PKs; bottom‐up). This was done through meta‐analyses and meta‐regressions in addition to theoretical PK simulations. Volumes of distribution and clearances were found to be elevated in people living with CF. These increases were larger in studies which included patients with pulmonary exacerbations. Differences in clearance were smaller in more recent studies and when results were normalized to body surface area or lean body mass instead of body weight. For the physiological parameters investigated, measured glomerular filtration rate and serum cytokine concentrations were found to be elevated in people living with CF, whereas serum albumin and creatinine levels were decreased. Possible pathophysiological mechanisms for these alterations relate to renal hyperfiltration, increases in free fraction, and inflammation. No differences were detected for cardiac output, body fat, fat free mass, hematocrit, creatinine clearance, and the activity of drug metabolizing enzymes. These findings imply that, in general, lower total plasma concentrations of drugs can be expected in people living with CF, especially when pulmonary exacerbations are present. Given the potential effect of CF on plasma protein binding and the variability in outcome observed between studies, the clinical relevance of adapting existing dosage regimens should be evaluated on a case‐by‐case basis.

Abstract 5422: Exploring the feasibility of longer dosing intervals in a population with relapsed/refractory classic Hodgkin's lymphoma based on population pharmacokinetics modeling analysis

Abstract Background: Penpulimab is a humanized IgG1 monoclonal antibody that blocks PD-1 binding to PD-L1. During the dose-escalation phase, no dose-limiting toxicity event was observed, and the maximum administered dose(MAD) was 10 mg/kg Q2W. The RO% of all dose groups (1.0, 3.0 and 10.0 mg/kg Q2W) reached 80%~100%. Penpulimab was administered in a fixed dosing regimen (200 mg Q2W) in a phase II study (AK105-201) demonstrating efficacy and safety in R/R cHL patients. Longer dosing intervals may offer greater flexibility and convenience to both patients and healthcare professionals. So we explored the feasibility of a longer dosing regimen (200 mg Q3W and 400 mg Q6W). Methods: A penpulimab population PK (PPK) model was established based on PK data from a total of 332 subjects from six clinical studies. The following PK parameters were determined and used in subsequent analyses: Cmin,ss, Cmax,ss, AUCss. Exposure-response (ER) evaluation was conducted using univariate logistic regression. The efficacy endpoints included complete response (CR), overall response rate (ORR) and disease control rate (DCR) in AK105-201 study. Safety endpoints included grade ≥ 3 treatment-related adverse event (TRAE), grade ≥ 3 immune-related adverse events (irAE), or AE leading to suspension in all the six clinical studies. PK simulation was conducted using the PPK model among different regimens (200 mg Q3W and 400 mg Q6W vs. 200 mg Q2w regimen), and in comparison with Cmin,ss of 3 μg/mL (6 x concentration for 80% RO in vitro). Result: The final PPK structural model for penpulimab was a two-compartment model with first-order elimination. Body weight correlated with volume of distribution but the effect is not considered clinically significant, supporting fixed dose in subsequent studies. Relatively flat ER relationships were observed betwedn the efficacy endpoints (CR, ORR and DCR) and PK exposure (simulated Cmax,ss, Cmin,ss, AUCss) in R/R cHL patients. No apparent correlation was observed between PK exposure and safety response in patients with different types of cancer. The PK simulation showed that the steady-state concentration-time curves for 200 mg Q2W or 3 mg/kg Q2W administration were generally consistent. Compared to the 200 mg Q2W regimen, the mean Cmin,ss of 200 mg Q3W and 400 mg Q6W regimens were approximately 36.5% and 55.5% lower, respectively. But in both cases, the Cmin,ss of 97.5% of the population were higher than 3 μg/mL, suggesting sufficient receptor occupancy. The Cmax,ss and AUCss under the 400 mg Q6W regimen were lower than MAD(10 mg/kg Q2W). Conclusions: The conducted analyses support fixed dosing and showed relatively flat exposure-efficacy and exposure-safety relationships. PK simulations suggest that both 200 mg Q3W or 400 mg Q6w could offer similar efficacy and safety as compared to 200 mg Q2W, while allow greater flexibility and convenience. Citation Format: Benchao Chen, Yongcheng Dong, Jin Xiao, Max Wang, Dennis Xia, Michelle Xia, Baiyong Li. Exploring the feasibility of longer dosing intervals in a population with relapsed/refractory classic Hodgkin's lymphoma based on population pharmacokinetics modeling analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5422.

A phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+ tumors: Interim results.

2583 Background: MT-5111 is a 55kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction. Methods: This is a phase 1 study in adults with advanced HER2+ solid tumors. The dose-escalation portion (Part A) enrolls pts into sequential dose cohorts, followed by Part B expansion cohorts for HER2+ breast cancer (BC), gastroesophageal adenocarcinoma (GEA), and any other HER2+ cancer (CA). MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death or withdrawn consent. Results: As of Jan 2022, 27 pts had enrolled in Part A cohorts (0.5 to 10 µg/kg/dose) with completed DLT assessments: 9 (33%) pts were male and 18 (67%) female, median age 67 and a median of 4 prior systemic and 2 prior HER2-targeting tx. Common tissue types were BC (9/30%), biliary CA (6/22%), GEA (4/15%). The following safety data reflect 33 treated pts to date including ongoing 13 µg/kg/dose Part A and 10 µg/kg/dose BC expansion cohorts. No Grade (G) 4/5 tx-emergent adverse events (AEs) or DLTs occurred. Tx-related AEs occurred in 17 (52%) pts, most commonly G1/2 fatigue (8/24%). 3 pts had G1 troponin elevations without clinical signs or symptoms of cardiac distress: 1 at 6.75 µg/kg/dose, 2 at 10 µg/kg/dose. 2 pts (3 and 4.5 µg/kg/dose) had reversible G2 and G1, respectively, infusion-related reactions (IRR)s. A comparison of cytokines from baseline to on-treatment timepoints reveals no evidence of significant changes, even in pts with IRR. Best response per RECIST thus far was stable disease (SD) in 7 pts or non-CR/non-PD in 2 pts: 1 pt had SD for 12 weeks (wks) (4.5 μg/kg, pancreatic CA); 1 pt (1 μg/kg/dose, BC) had non-CR/non-PD for 30 wks; 1 pt (10 μg/kg/dose, GEA) has ongoing SD for 18 wks. AUClast data match PK simulations in non-human primate studies. Cmax at 10 µg/kg/dose is ≥5 times the IC50 values of high HER2 expressing gastric CA and BC cell lines while approaching the IC50 of a moderately HER2 expressing liver CA cell line. Conclusions: MT-5111 is well tolerated to-date with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing at a dose of 13µg/kg, expected to be required for efficacious exposure. Clinical trial information: NCT04029922.

A phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+tumors: Interim results.

297 Background: MT-5111 is a 55 kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction and does not rely on inhibition of kinase signaling or cytoskeletal or DNA damage. Methods: This is a phase 1 study in adult pts with advanced HER2+ solid tumors. The dose-escalation portion (modified 3+3 design) enrolls pts into sequential cohorts followed by expansion cohorts for HER2+ breast cancer (BC), gastric or gastroesophageal junction adenocarcinoma (GEA), and other HER2+ tumors. MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death, or withdrawn consent. Results: As of Sep 2021 (contains preliminary data), 24 pts (mean age 64 yrs) were treated, 13 (54%) of whom had gastrointestinal (GI) tumors (6 biliary, 3 GEA, 2 pancreatic, 2 colo/rectal) (Table). Pts with GI tumors had a median of 3 prior systemic tx and 1 prior HER2-targeting tx. No Grade (G) 4/5 tx-emergent adverse events (AEs) occurred. Tx-related AEs occurred in 13 (54%) pts, most commonly fatigue (n=7, 29%). One pt with biliary cancer and concurrent lymphangitic carcinomatosis and H. influenzae infection (4.5 µg/kg) had a possibly related G3 serious AE (SAE) of dyspnea, which resolved 9 days later. Another related SAE occurred in a pt with GEA (6.75 µg/kg) who had a G1 transient troponin increase that resolved during hospitalization, with no clinical symptoms or ECG/ECHO changes; the pt withdrew from study before further dosing. All other related AEs were ≤G2. No other clinically significant changes in cardiac biomarkers (troponin, ECG, LVEF) or cases of capillary leak syndrome occurred. Two pts (3 and 4.5 µg/kg) had reversible G2 infusion-related reactions. Best response to date has been stable disease. AUClast data matched PK simulations based on non-human primate studies. Cmax data at 10 µg/kg indicate that current in-pt exposure was between IC50 values of high and medium HER2-expressing cell lines (approx 10-89 ng/mL). Thus, at least 10 µg/kg may be required to achieve effective exposure. No dose-limiting toxicities have been observed. The 10 µg/kg cohort is now accruing. Following this cohort, an expansion cohort for pts with BC will open. Conclusions: MT-5111 was well tolerated with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing and is nearing levels expected to be required for efficacious exposure. Clinical trial information: NCT04029922. [Table: see text]

DallphinAtoM: Physiologically based pharmacokinetics software predicting human PK parameters based on physicochemical properties, in vitro and animal in vivo data

Background and objectivesIn silico experiments and simulations using physiologically based pharmacokinetic (PBPK) and allometric approaches have played an important role in pharmaceutical research and drug development. These methods integrate diverse data from preclinical and clinical development, and have been widely applied to in vitro-in vivo extrapolation (IVIVE) of absorption, distribution, metabolism, and excretion (ADME). MethodsTo develop a user-friendly open tool predicting human PK, we assessed various references on PBPK and allometric methods published so far. They were integrated into a software system named “DallphinAtoM” (Drugs with ALLometry and PHysiology Inside-Animal to huMan), which has a user-friendly platform that can handle complex PBPK models and allometric models with a relatively small amount of essential information of the drug. The models of DallphinAtoM support the integration of data gained during the nonclinical development phase, enable translation from animal to human, and allow the prediction of concentration-time profiles with predicted PK parameters. ResultsWe presented two illustrative applications using DallphinAtoM: (1) human PK simulation of an orally administered drug using PBPK method; and (2) simulation of intravenous infusion following a two-compartment model using the allometric scaling method. ConclusionsWe conclude that this is a straightforward and transparent tool allowing fast and reliable human PK simulation based on the latest knowledge on biochemical processes and physiology and provides valuable information for decision making during the early-phase drug development.

Rationale for the Clinical Use of Less Frequent Dosing of Mogamulizumab for T-Cell Lymphomas Using Population Pharmacokinetic and Exposure Response Analysis

▪Background: CC chemokine receptor 4 (CCR4) is expressed on several T cell subsets and is implicated in the pathogenesis of a variety of leukemias and lymphomas. Mogamulizumab is a humanized monoclonal antibody targeting CCR4 receptors and is indicated for treatment of adult patients with cutaneous T-cell lymphoma (relapsed or refractory mycosis fungoides or Sézary syndrome). The objectives of these analyses were to (1) develop a population pharmacokinetics (PPK) model to characterize mogamulizumab PK following administration to subjects who have lymphomas or solid tumors, (2) evaluate patient covariates that influence the variability in PK, (3) simulate mogamulizumab PK at 2 mg/kg every four weeks (Q4W) dosing and compare with the PK at 1 mg/kg every two weeks (Q2W) dosing and (4) assess the exposure-response (ER) relationship between mogamulizumab exposures and adverse events (AEs). A Phase 2 clinical study is ongoing to obtain PK, efficacy, and safety data for 2 mg/kg Q4W dosing (NCT04745234).Methods: Plasma or serum pharmacokinetic data from 525 subjects with cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), adult T-cell leukemia-lymphoma (ATL), or solid tumors were included in this analysis. Mogamulizumab was administered over 0.01 mg/kg to 3 mg/kg dose range as mono- or combination-therapy. Nonlinear mixed effects modeling was used to develop a base PPK model followed by covariate evaluation. Simulations were performed to estimate exposure metrics to support ER analyses and to compare 2 mg/kg Q4W and 1 mg/kg Q2W dosing scenarios following four 1 mg/kg weekly doses in the first cycle of treatment. Comparisons between mogamulizumab exposures and grade 3 and grade 4 AEs were conducted.Results: A two-compartment PPK model with linear elimination and log-normal variability on clearance and the volumes of distribution of the central and peripheral compartments, described the PK data. Body weight, albumin, and tumor type were identified as statistically significant covariates affecting mogamulizumab exposure. Other covariates that were tested but did not demonstrate statistically significant effect on mogamulizumab exposure included age, race, creatinine clearance, degree of CCR4 expression, combination- vs. mono-therapy, CTCL subtype (when applicable), and mild hepatic impairment. The PK simulations demonstrated that the overall exposures (AUC ss) achieved with mogamulizumab 2 mg/kg Q4W dosing were comparable to mogamulizumab 1 mg/kg Q2W dosing, with C max predicted to be 47% greater and C min to be 29% lower. Evaluations of dose and exposure (AUC ss, C max, C min) vs. incidence of grade 3 and grade 4 AEs showed no relationship.Conclusions: The PPK model adequately characterized the mogamulizumab PK over the doses ranging from 0.01 to 3 mg/kg. There was no relationship between the exposure of mogamulizumab and the emergence of grade 3 or grade 4 AEs across the dose range explored. Thus, the mogamulizumab 2 mg/kg Q4W dosing is not expected to lead to increased incidences of grade 3 and grade 4 AEs. From a PK and safety perspective, this analysis supports 2 mg/kg Q4W Mogamulizumab as an appropriate alternative dosing strategy to the approved, 1 mg/kg Q2W, dosing posology in T-cell lymphomas.Acknowledgements: We would like to express special appreciation to Dr. Roland Meier, MD, PhD, for sponsoring this abstract. DisclosuresMehta: Kyowa Kirin: Current Employment. Patel: Kyowa Kirin: Current Employment. Vuppugalla: Kyowa Kirin: Current Employment. Tudor: Kyowa Kirin: Current Employment. Dwyer: Kyowa Kirin: Current Employment; Bristol Myers Squibb: Current Employment. Hruska: Viatris: Current equity holder in publicly-traded company; Viking: Current equity holder in publicly-traded company; Durect: Current equity holder in publicly-traded company; CymaBay: Current equity holder in publicly-traded company; Takeda: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Johnson & Johnson: Current equity holder in publicly-traded company; GlaxoSmithKline: Current equity holder in publicly-traded company; Genmab: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Biohaven: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current equity holder in publicly-traded company; Kyowa Kirin: Current Employment. Marsteller: Kyowa Kirin: Current Employment. OffLabel Disclosure:Yes. Mogamulizumab is a CCR4-directed monoclonal antibody indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least one prior systemic therapy - new dosing regimen under examination.