Selection Of Dosing Regimen Research Articles

Population Pharmacokinetics of Trofinetide in a Pediatric Population Aged 2-4Years with Rett Syndrome.

Weight-banded trofinetide dosing improved physician- and caregiver-rated efficacy measures and had acceptable tolerability in patients aged 2‒4years (DAFFODIL study) and 5‒20years (LAVENDER study) with Rett syndrome (RTT). Selection of weight-banded dosing regimens for these studies was based on population pharmacokinetic (popPK) modeling and exposure simulations. This study applied an updated popPK model to confirm steady-state trofinetide exposures achieved in DAFFODIL patients were within target range. A popPK model was developed using data from 14 clinical studies of trofinetide in healthy volunteers and pediatric and adult patients, including the LAVENDER and DAFFODIL studies. Individual exposure measures (area under concentration-time curve over 0-12h [AUC0-12] were generated via integration of the predicted concentration-time profile for each DAFFODIL study participant based on the popPK model and individual empiric Bayesian pharmacokinetic parameter estimates. Distributions of steady-state AUC0-12 values for each body-weight group were compared against target exposure (AUC0-12 = 800‒1200µg·h/mL). Distribution and box plots of simulated steady-state AUC0-12 values achieved with the weight-banded DAFFODIL dosing regimen used in younger individuals aged 2-4years with RTT (twice daily trofinetide 5g[≥ 9 to < 12kg] or 6g [≥ 12 to < 20kg]) indicated good overlap with the target exposure range. Median steady-state AUC0-12 values for both body-weight bands fell within the target exposure range. PopPK model-based simulations confirm that the weight-banded dosing regimen used in DAFFODIL is adequate to achieve target trofinetide exposure in 2- to 4-year-olds with RTT.

Dosing of Venetoclax in Pediatric Patients with Relapsed Acute Myeloid Leukemia: Analysis of Developmental Pharmacokinetics and Exposure-Response Relationships

This work aimed to characterize the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) to identify venetoclax doses to be administered to pediatric patients in the phase 3 study. Data from 121 patients across three phase 1 studies enrolling pediatric patients with R/R malignancies were utilized to develop a population pharmacokinetic model to describe venetoclax pharmacokinetics in pediatric patients. Individual patient average venetoclax plasma concentration up to the event of interest, derived based on the population pharmacokinetics analysis, was used to evaluate the exposure-response relationships to efficacy (complete response) and safety (neutropenia and thrombocytopenia) endpoints for patients with AML who received venetoclax in combination with azacitidine, decitabine, or cytarabine (n = 36). The population pharmacokinetic model was then used to simulate exposures in pediatric age- and weight-based subgroups to identify the venetoclax doses for pediatric patients. The pharmacokinetic data were adequately described by the two-compartment population pharmacokinetic model with first-order absorption and elimination. The model accounted for cytochrome P450 3A developmental changes using a maturation function and incorporated allometric scaling to account for growth and body size effect. Weight was identified as a statistically significant covariate on clearance and volume of distribution and retained in the final model. Population pharmacokinetic estimates were comparable to previously reported estimates in adults. Exposure-response analyses suggested that the clinical efficacy of venetoclax in combination with high-dose cytarabine (HDAC) is maximized at 600 mg adult-equivalent, and higher doses are unlikely to enhance clinical efficacy. Venetoclax 600 mg adult-equivalent was selected for further development in combination with HDAC. Additionally, venetoclax 400 mg adult-equivalent was selected for bridging/maintenance therapy in combination with azacitidine. Flat exposure-response relationships were observed with Grade ≥3 neutropenia and thrombocytopenia. Doses were selected based on weight (allometric scaling) for children aged ≥2 years old and based on weight and CYP3A ontogeny for children aged <2 years. The selected age- and weight-based dosing scheme of venetoclax is projected to achieve venetoclax exposures in pediatric subgroups comparable to those observed in adults receiving venetoclax 400 mg or 600 mg. This work characterized the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients and guided the selection of pediatric dosing regimens in support of the venetoclax phase 3 trial in pediatric AML (NCT05183035). NCT03236857, NCT03181126, and NCT03194932.

Towards clinically relevant dose ratios for Cabamiquine and Pyronaridine combination using P. falciparum field isolate data

The selection and combination of dose regimens for antimalarials involve complex considerations including pharmacokinetic and pharmacodynamic interactions. In this study, we use immediate ex vivo P. falciparum field isolates to evaluate the effect of cabamiquine and pyronaridine as standalone treatments and in combination therapy. We feed the data into a pharmacometrics model to generate an interaction map and simulate meaningful clinical dose ratios. We demonstrate that the pharmacometrics model of parasite growth and killing provides a detailed description of parasite kinetics against cabamiquine-susceptible and resistant parasites. Pyronaridine monotherapy provides suboptimal killing rates at doses as high as 720 mg. In contrast, the combination of a single dose of 330 mg cabamiquine and 360 mg pyronaridine provides over 90% parasite killing in most of the simulated patients. The described methodology that combines a rapid, 3R-compliant in vitro method and modelling to set meaningful doses for new antimalarials could contribute to clinical drug development.

Model-informed drug development of envafolimab, a subcutaneously injectable PD-L1 antibody, in patients with advanced solid tumors.

Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody for the treatment of instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors in adults, including those with advanced colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The aim of this investigation was to examine the pharmacokinetic and exposure-response (E-R) profile of envafolimab in patients with solid tumors to support the approval of fixed and alternative dose regimens. In this study, a population pharmacokinetic (PopPK) modeling approach will be employed to quantitatively evaluate intrinsic and extrinsic covariates. Additionally, PopPK-estimated exposure parameters were used to evaluate E-R relationship for safety and efficacy to provide a theoretical basis for recommending optimal treatment regimens. Simulations were performed on the dosing regimens of body weight-based regimen of 2.50 mg/kg QW, fixed dose 150 mg QW, and 300 mg Q2W for the selection of alternative dosing regimens. Data from 4 clinical studies (NCT02827968, NCT03101488, NCT03248843, and NCT03667170) were utilized. The PopPK dataset comprised 182 patients with 1810 evaluable envafolimab concentration records. Finally, a one-compartment model incorporating first-order absorption, first-order linear elimination, and time-dependent elimination according to an Emax function was found to accurately describe the concentration-time data of envafolimab in patients with advanced solid tumors. Creatinine clearance and country were identified as statistically significant factors affecting clearance, but had limited clinical significance. A relative flat exposure-response relationship was observed between early measures of safety and efficacy to verify that no dose adjustment is required. Simulation results indicated that 2.50 mg/kg QW, 150 mg QW, and 300 mg Q2W regimen yield similar steady-state exposure. No statistically significant difference was observed between weight-based and fixed dose regimens. Model-based simulation supports the adoption of a 150 mg weekly or 300 mg biweekly dosing regimen of envafolimab in the solid tumor population, as these schedules effectively balance survival benefits and safety risks.

Population pharmacokinetics of nirmatrelvir in Chinese patients with COVID-19: Therapeutic drug monitoring and dosing regimen selection in clinical practice

ObjectivesTo establish a population pharmacokinetics (PopPK) model of nirmatrelvir in Chinese COVID-19 patients and provide reference for refining the dosing strategy of nirmatrelvir in patients confirmed to be infected with SARS-CoV-2. MethodsA total of 80 blood samples were obtained from 35 mild to moderate COVID-19 patients who were orally administered nirmatrelvir/ritonavir tablets. The PopPK model of nirmatrelvir was developed using a nonlinear mixed effects modelling approach. The stability and prediction of the final model were assessed through a combination of goodness-of-fit and bootstrap method. The exposure of nirmatrelvir across various clinical scenarios was simulated using Monte Carlo simulations. ResultsThe pharmacokinetics of nirmatrelvir was well characterised by a one-compartment model with first-order absorption, and with creatinine clearance (Ccr) as the significant covariate. Typical population parameter estimates of apparent clearance and distribution volume for a patient with a Ccr of 95.5 mL·min−1were 3.45 L·h−1 and 48.71 L, respectively. The bootstrap and visual predictive check procedures demonstrated satisfactory predictive performance and robustness of the final model. ConclusionThe final model was capable of offering an early prediction of drug concentration ranges for different nirmatrelvir dosing regimens and optimise the dose regimen of nirmatrelvir in individuals with confirmed SARS-CoV-2 infection.

PHARMACOGENETICS OF ANESTHESIOLOGICAL SUPPORT

Pharmacogenetics studies the relationship between a person’s individual genetic characteristics and the human body’sresponse to the action of various drugs, particularly the occurrence of undesirable side eff ects. Thanks to the development of the latest technologies and methods, this branch of medical genetics and clinical pharmacology is developing very actively. Data are being accumulated, special databases are being created with the aim of creating individual genetic passports in the future, which will allow the selection of personalized treatment schemes.Anesthesiology is a special area of pharmacogenetic research because, more than any other medical specialty, it ischaracterized by polypharmacy-the simultaneous or sequential administration of many drugs. The same dose of a drug may be inadequate for some patients and may be life-threatening or cause unwanted side eff ects for others. Today, information about genetic factors is being used by clinicians to prescribe drugs to tailor drug therapy to a patient’s genome. In anesthesiology, the principles of pharmacogenetics have been explained for neuromuscular blocking agents, opioid metabolism, different types of anesthetics, and postoperative nausea and vomiting. On the other hand, a large number of anesthetics have a narrow therapeutic index.This review summarizes the most recent data from the scientifi c literature on the pharmacogenetics of diff erent types ofanesthetics. Inhalational anesthetics are halogenated derivatives of methyl ethyl ether, the exact mechanism of action of which is not yet fully understood. One of the rare but very serious side eff ects of all halogenated anesthetics is malignant hyperthermia, a genetically determined autosomal dominant disorder that manifests as a hypermetabolic response to drug administration. The dosage of intravenous anesthetics should also be carefully determined, taking into account the patient’s age, cardiovascular, hepatic, and renal status, concomitant drug therapy, and genetic factors. Ontogeny and genetic variability of drug-metabolizing enzymes are interrelated because genetic variability in drug-metabolizing enzyme expression cannot be assessed until the required protein is suffi ciently expressed. Pharmacogenetic variants may contribute to unpredictable drug exposure at the same weight- based drug dose.There are a number of potentially clinically applicable pharmacogenetic data in newborns, but more research is needed toconfi rm these fi ndings and understand how to incorporate them into clinical care.The selection of drugs and dosing regimens based on a patient’s pharmacogenomic profi le may be an important part of thefuture of medicine. Personalized treatment based on the specifi c variants in the genome will ultimately reduce the incidence of side eff ects and length of hospital stay for patients and save healthcare costs. Although pharmacogenomics and its application in clinical practice are still in their infancy, different variants and their implications for many clinical areas, including anesthesiology, are emerging every day.

Model-Based Dose Selection of Subcutaneous Nivolumab in Patients with Advanced Solid Tumors.

The pharmacokinetics (PK) of intravenous (i.v.) nivolumab is well characterized. A subcutaneous (s.c.) nivolumab formulation with and without recombinant human hyaluronidase PH20 enzyme is being evaluated in CheckMate 8KX (NCT03656718). A model-based analysis was conducted to characterize the PKof nivolumab s.c. and predict systemic exposures after i.v. and s.c. administration to guide dosing regimen selection for nivolumab s.c. A prior i.v. model was modified to incorporate an s.c. extravascular compartment and estimate the absorption rate constant and bioavailability of nivolumab s.c. Serum concentration-time data from 82 patients treated with nivolumab s.c. 720, 960, or 1,200 mg were pooled with existing i.v. data from multiple studies for model development. Prediction-corrected visual predictive check (pcVPC) plots assessed the model's performance. Stochastic simulations were conducted to predict exposures for i.v. and s.c. administration. The data were described by a two-compartment model with time-varying clearance, zero-order infusion into the central compartment after i.v. dosing, and first-order absorption from the extravascular compartment after s.c. dosing. The pcVPC suggested that the model adequately described the observed nivolumab s.c. data. Predicted nivolumab exposures at 1,200 mg s.c. every 4 weeks (q4w) were higher than those at the approved dose of 3 mg/kg i.v. q2w and lower than those at the highest tested safe dose of 10 mg/kg i.v. q2w. Nivolumab PK is well-characterized using the combined s.c./i.v. population PK model. The model-based analysis facilitated a comprehensive benefit-risk assessment of nivolumab s.c. and informed selection of 1,200 mg s.c. q4w for phase III evaluation.

Clinical Pharmacology Approaches to Support Approval of New Routes of Administration for Therapeutic Proteins.

Intravenous or subcutaneous routes of administration (ROAs) are common dosing routes for therapeutic proteins. Eleven therapeutic proteins with approval for one ROA have subsequently received approval for a second ROA. The clinical programs supporting the second ROA consistently leveraged data from the first ROA and included studies that characterized the pharmacokinetics (PKs) of the drug administered by the new ROA to identify an appropriate dosage regimen. The selected dosing regimen was then further evaluated in clinical trials designed with various primary end points. All programs implemented model-informed drug development approaches to ensure that the selected regimens would achieve comparable systemic exposures (PK-based bridging) or pharmacodynamic (PD) responses (PD-based bridging) as the reference ROA. To support the approval of a second ROA, these programs either demonstrated noninferiority in PK, PD, and/or clinical end points for the second ROA, or established efficacy and safety through a comparison to a placebo treatment. The accumulative examples showed that clinical trials which provided the primary evidence to support approvals of the second ROA generally demonstrated noninferiority in the systemic exposures regardless of being specified as an end point or not in the study protocols. The experience to date supports the use of PK- and PD-based bridging approaches not only in the selection of dosing regimens for a second ROA to be tested in clinical studies, but also for providing evidence of effectiveness to support approval, when appropriate.

Model-Based Benefit/Risk Analysis for the Copanlisib Intermittent Dosing Regimen.

Copanlisib is an intravenously administered phosphatidylinositol 3-kinase (PI3K) inhibitor, which is approved as monotherapy for relapsed follicular lymphoma in adult patients who have received at least two systemic therapies. In an April 2022 US Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC), the benefit-risk profile of the class PI3K inhibitors were scrutinized for use in hematological malignancies. Specifically, their unique toxicities may contribute to the high incidences in reported serious and high-grade treatment emergent adverse events (TEAEs), thereby reducing their overall tolerability and potentially limiting their successful use. These tolerability concerns may be contributed by or compounded by inadequate dose optimization. The recommended dosing regimen of copanlisib 60 mg administered on days 1, 8, and 15 of a 28-day cycle was selected as the maximal tolerated dose (MTD) during phase I. Thus, this analysis sought to justify the copanlisib dose regimen selection. Copanlisib exposure-efficacy relationships were considered from its large phase III trial, CHRONOS-3, whereas copanlisib safety was investigated by pooling data across its two large clinical trials to comprehensively assess its exposure-safety relationships. Results demonstrated a statistically significant positive linear exposure-efficacy relationship at the MTD. Exposure-safety analyses revealed a borderline significant linear relationship for grade ≥3 TEAEs and no significant exposure-safety relationships for other investigated safety end points. The model-based benefit/risk framework considered the established exposure-response models and defined clinical utility function which confirmed the appropriateness of the copanlisib dosing regimen across the range of its achieved exposures.

A Mechanistic Physiologically-Based Pharmacokinetic Platform Model to Guide Adult and Pediatric Intravenous and Subcutaneous Dosing for Bispecific T Cell Engagers.

Bispecific T cell engagers (Bi-TCEs) have revolutionized the treatment of oncology indications across both liquid and solid tumors. Bi-TCEs are rapidly evolving from conventional intravenous (i.v.) to more convenient subcutaneous (s.c.) administrations and extending beyond adults to also benefit pediatric patients. Leveraging clinical development experience across three generations of Bi-TCE molecules across both liquid and solid tumor indications from i.v./s.c. dosing in adults and pediatric subjects, we developed a mechanistic-physiologically-based pharmacokinetic (PBPK) platform model for Bi-TCEs. The model utilizes a full PBPK model framework and was successfully validated for PK predictions following i.v. and s.c. dosing across both liquid and solid tumor space in adults for eight Bi-TCEs. After refinement to incorporate physiological ontogeny, the model was successfully validated to predict pediatric PKs in 1 month - < 2 years, 2-11 years, and 12-17 years old subjects following i.v. dosing. Following s.c. dosing in pediatric subjects, the model predicted similar bioavailability, however, a shorter time to maximum concentration (Tmax ) for the three age groups compared with adults. The model was also applied to guide the dosing strategy for first generation of Bi-TCEs for organ impairment, specifically renal impairment, and was able to accurately predict the impact of renal impairment on PK for these relatively small-size Bi-TCEs. This work highlights a novel mechanistic platform model for accurately predicting the PK in adult and pediatric patients across liquid and solid tumor indications from i.v./s.c. dosing and can be used to guide optimal dose and dosing regimen selection and accelerating the clinical development for Bi-TCEs.

Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition.

The phase 2b proof-of-concept Antibody Mediated Prevention (AMP) trials showed that VRC01, an anti-HIV-1 broadly neutralising antibody (bnAb), prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, we investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data. The case-control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study. We measured VRC01 serum concentrations with a qualified pharmacokinetic (PK) Binding Antibody Multiplex Assay. We employed nonlinear mixed effects PK modelling to estimate daily-grid VRC01 concentrations. Cox regression models were used to assess the association of VRC01 concentration at exposure and baseline body weight, with the hazard of HIV-1 acquisition and prevention efficacy as a function of VRC01 concentration. We also compared fixed dosing vs. body weight-based dosing via simulations. Estimated VRC01 concentrations in VRC01 recipients without HIV-1 were higher than those in VRC01 recipients who acquired HIV-1. Body weight was inversely associated with HIV-1 acquisition among both placebo and VRC01 recipients but did not modify the prevention efficacy of VRC01. VRC01 concentration was inversely correlated with HIV-1 acquisition, and positively correlated with prevention efficacy of VRC01. Simulation studies suggest that fixed dosing may be comparable to weight-based dosing in overall predicted prevention efficacy. These findings suggest that bnAb serum concentration may be a useful marker for dosing regimen selection, and operationally efficient fixed dosing regimens could be considered for future trials of HIV-1 bnAbs. Was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Center [FHCC]; 2R37 054165 to the FHCC; UM1 AI068618, to HVTN Laboratory Center, FHCC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, Duke University (AI P30 AI064518) and University of Washington (P30 AI027757) Centers for AIDS Research; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC Bill & Melinda Gates Foundation.

Model-Informed Support of Dose Selection for Prophylactic Treatment with Dalcinonacog Alfa in Adult and Paediatric HemophiliaB Patients.

Dalcinonacog alfa (DalcA), a novel subcutaneously administered recombinant human factorIX (FIX) variant is being developed for adult and paediatric patients with hemophiliaB (HB). DalcA has been shown to raise FIX to clinically meaningful levels in adults with HB. This work aimed to support dosing regimen selection in adults and perform first-in-paediatric dose extrapolations using a model-based pharmacokinetic (PK) approach. A population PK model was built using adult data from two clinical trials (NCT03186677, NCT03995784). With allometry in the model, clinical trial simulations were performed to study alternative dosing regimens in adults and children. Steady-state trough levels and the time-to-reach target were derived to inform dose selection. Almost 90% of the adults were predicted to achieve desirable FIX levels, i.e. 10% FIX activity, following daily 100IU/kg dosing, with 90% of the subjects reaching target within 1.6-7.1days. No every-other-day regimen met the target. A dose of 125IU/kg resulted in adequate FIX levels down to 6years, whereas a 150IU/kg dose was needed below 6 down to 2years of age. For subjects down to 6years that did not reach target with 125IU/kg, a dose escalation to 150IU/kg was appropriate. The children below 6 to 2years were shown to need a dose escalation to 200IU/kg if 150IU/kg given daily was insufficient. This study supported the adult dose selection for DalcA in the presence of sparse data and enabled first-in-paediatric dose selection to achieve FIX levels that reduce risk of spontaneous bleeds.

Optimal dosing regimen of CD73 blockade improves tumor response to radiotherapy through iCOS downregulation

BackgroundIrradiation (IR) and immune checkpoint inhibitor (ICI) combination is a promising treatment modality. However, local and distance treatment failure and resistance can occur. To counteract this resistance, several studies propose...

Sabatolimab (MBG453) model-informed drug development for dose selection in patients with myelodysplastic syndrome/acute myeloid leukemia and solid tumors.

Sabatolimab is a novel immunotherapy with immuno-myeloid activity that targets T-cell immunoglobulin domain and mucin domain-3 (TIM-3) on immune cells and leukemic blasts. It is being evaluated for the treatment of myeloid malignancies in the STIMULUS clinical trial program. The objective of this analysis was to support the sabatolimab dose-regimen selection in hematologic malignancies. A population pharmacokinetic (PopPK) model was fit to patients with solid tumors and hematologic malignancies, which included acute myeloid leukemia, myelodysplastic syndrome (including intermediate-, high-, and very high-risk per Revised International Prognostic Scoring System), and chronic myelomonocytic leukemia. The PopPK model, together with a predictive model of sabatolimab distribution to the bone marrow and binding to TIM-3 was used to predict membrane-bound TIM-3 bone marrow occupancy. In addition, the total soluble TIM-3 (sTIM-3) kinetics and the pharmacokinetic (PK) exposure-response relationship in patients with hematologic malignancies were examined. At intravenous doses above 240 mg Q2w and 800 mg Q4w, we observed linear PK, a plateau in the accumulation of total sTIM-3, and a flat exposure-response relationship for both safety and efficacy. In addition, the model predicted membrane-bound TIM-3 occupancy in the bone marrow was above 95% in over 95% of patients. Therefore, these results support the selection of the 400 mg Q2w and 800 mg Q4w dosing regimens for the STIMULUS clinical trial program.

A Pharmacometrics Model to Characterize a New Type of Target-Mediated Drug Disposition (TMDD) - Nonlinear Pharmacokinetics of Small-Molecule PF-07059013 Mediated By Its High-capacity Pharmacological Target Hemoglobin With Positive Cooperative Binding.

In general, small-molecule target-mediated drug disposition (TMDD) is caused by the interaction of a drug with its high-affinity, low-capacity pharmacological target. In the current work, we developed a pharmacometrics model to characterize a new type of TMDD, where the nonlinear pharmacokinetics (PK) is mediated by a high-capacity pharmacological target with cooperative binding instead of target saturation. The model drug we used was PF-07059013, a noncovalent hemoglobin modulator that demonstrated promising preclinical efficacy to treat sickle cell disease (SCD), and showed complex nonlinear PK in mice with the fraction of unbound drug in blood (fub) decreased with an increase in PF-07059013 concentrations/doses due to the positive cooperative binding of PF-07059013 to hemoglobin. Among the various models we evaluated, the best one is a semi-mechanistic model where only drug molecules not bound to hemoglobin were allowed for elimination, with the nonlinear pharmacokinetics being captured by incorporating cooperative binding for drug molecules bound to hemoglobin. Our final model provided valuable insight on target binding-related parameters, such as the Hill coefficient γ (estimated to be 1.6), binding constant KH (estimated to be 1450 µM), and the amount of total hemoglobin Rtot (estimated to be 2.13 µmol). As the dose selection of a compound with positive cooperative binding is tricky and challenging due to the nonproportional and steep response, our model may be valuable in facilitating the rational dose regimen selection for future preclinical animal and clinical trials for PF-07059013 and other compounds whose nonlinear pharmacokinetics are caused by similar mechanisms.

Model-based simulation to support the approval of isatuximab alone or with dexamethasone for the treatment of relapsed/refractory multiple myeloma in Japanese patients.

This study aimed to support dosing regimen selection for isatuximab as a single agent or in combination with dexamethasone for Japanese patients with relapsed/refractory multiple myeloma (RRMM). A joint model characterizing the dynamics of serum M-protein kinetics and its association with progression-free survival (PFS) was developed using data from 201 evaluable Japanese and non-Japanese patients with RRMM enrolled in two monotherapy phase I/II trials, where Japanese patients (n= 31) received isatuximab at 10 or 20 mg/kg once weekly (qw) for 4 weeks then every 2 weeks (q2w) in subsequent cycles (10 or 20 mg/kg qw-q2w). Among non-Japanese patients, 38 received isatuximab 20 mg/kg qw-q2w in combination with dexamethasone. Trial simulations were then performed to evaluate the effect of the isatuximab dosing regimens on both serum M-protein and PFS with and without dexamethasone. The model identified instantaneous changes in serum M-protein as the best on-treatment predictor for PFS. Trial simulations demonstrated that 20 mg/kg qw-q2w induced a greater decrease (30% vs. 22%) of serum M-protein at week 8 and prolonged median PFS by 2.4 weeks compared with 10mg/kg qw-q2w. Although Japanese patients did not receive isatuximab plus dexamethasone in the phase I/II trial, simulations predicted that isatuximab 20 mg/kg qw-q2w plus dexamethasone would induce a greater decrease (67% vs. 43%) of serum M-protein and a prolonged median PFS by 7.2 weeks compared with isatuximab alone. Trial simulations support the approved isatuximab 20 mg/kg qw-q2w regimen when administered as a single agent and in combination with dexamethasone in Japanese patients.

Population Pharmacokinetic and Exposure-Response Analyses for Efficacy and Safety of Risankizumab in Patients With Active Crohn's Disease.

The population pharmacokinetics (PK) of risankizumab and exposure-response relationships for efficacy and safety in patients with Crohn's disease (CD) were characterized using data from phase II and III studies to support dosing regimen selection. A two-compartment model with first-order absorption and first-order elimination adequately described risankizumab PK. Covariates including sex, baseline fecal calprotectin, corticosteroid use, baseline creatinine clearance, body weight, and baseline albumin were statistically correlated with risankizumab clearance, but their impact on exposure was not clinically relevant for efficacy or safety. Exposure-response analyses showed that exposures associated with the 600 mg intravenous (i.v.) induction dose at Weeks 0, 4, and 8 achieved a near maximal response for all efficacy end points evaluated, with negligible added benefit from the 1,200 mg i.v. regimen. By Week 52 of the maintenance treatment, trends of higher responses were observed for the exposure range associated with the 360 mg subcutaneous (s.c.) every-8-weeks (Q8W) regimen for most of the evaluated efficacy end points, particularly for the more stringent end points, such as endoscopic remission and ulcer-free endoscopy. Exposure-response analyses for safety did not identify any apparent relationship between exposure and safety. These results supported the final dose recommendation of 600 mg i.v. at Weeks 0, 4, and 8, followed by 360 mg s.c. at Week 12 and Q8W thereafter in patients with CD.

Translational Pharmacokinetic/Pharmacodynamic Model for mRNA-3927, an Investigational Therapeutic for the Treatment of Propionic Acidemia.

Propionic acidemia (PA) is an ultrarare disorder caused by deficiency of the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), composed of PCCA and PCCB subunits. An enzyme replacement therapy is being developed using dual messenger RNA (mRNA) therapy composed of lipid nanoparticles (LNPs) encapsulating mRNAs encoding PCCA and PCCB subunits of the PCC enzyme. We herein report on development of a translational semimechanistic pharmacokinetic (PK) and PK/pharmacodynamic (PD) model to quantify the relationship between the mRNA components of mRNA-3927 (an LNP encapsulating PCCA and PCCB mRNAs) and dose levels; PCCA/B mRNA PK and PD responses were assessed as circulating levels of primary disease markers 2-methyl citrate, 3-hydroxypropionate, and propionyl carnitine normalized to acetyl carnitine (C3/C2 ratio) to inform the first-in-human dose range and regimen selection. The translational PK/PD model was developed using preclinical data available in mice with PA, Sprague Dawley rats, and cynomolgus monkeys at dose levels ranging from 0.2 to 9 mg/kg. PCCA/B mRNA PK in mice, rats, and monkeys was adequately described using allometric scaling of volume and clearance parameters. The interspecies preclinical model was scaled allometrically to humans to predict the dose-response relationship in adult and pediatric patients with PA to guide selection of dose range and regimen for the Phase 1 clinical trial (ClinicalTrials.gov Identifier NCT04159103).

Pharmacokinetic-pharmacodynamic model to predict drug concentrations and intraocular pressure lowering effect for a bimatoprost six-month slow-release system.

Ophthalmic drug product development and dosing regimen selection depend on animal eye drug concentration-effect relationships since human eye tissues cannot be sampled for drug quantification. This study hypothesized that a pharmacokinetic-pharmacodynamic (PK-PD) mathematical model developed based on dog studies can be applied to the human eye of different ages, based on physiological parameter adjustment, to predict drug concentrations and effects in response to a new 6-month slow-release, intracameral, intraocular pressure (IOP) lowering, anti-glaucoma bimatoprost implant. Using previously reported dog concentration-effect relationship data at various doses, and the physiological parameters of dog eye, a PK-PD model was designed to predict dog aqueous humor drug concentrations and IOP lowering effects simultaneously for a given dose. After validating the model using the dog IOP data, it was applied to the human eye. Using a drug release rate constant of 0.0002 h-1, the model predicted the dog IOP lowering effect with an error less than 6% or less at various doses (Observed = 0.91*Predicted + 2.35; R2 = 0.98). Considering literature reported aqueous humor volumes and flow rates in old (over 60 years) and young (20 to 30 years) humans, aqueous humor elimination rate constant was estimated to be 0.9 and 0.68 h-1, respectively. The model when modified using the older human eye parameters, predicted the IOP lowering effects reported in a clinical trial with 63-year-old adults, with an error of 6.2% or less. The model, when used for young adult eye not previously tested in clinical trials, predicted lower drug concentrations and effects, possibly due to 54% higher aqueous humor volume relative to older adults. The model predicted an IOP reduction of 26.3 and 30.6%, at 10 and 15 microgram doses, respectively, in young adults. The PK-PD model developed is useful for product design and patient dosing by predicting eye drug concentration and effect time-courses in response to implant administration at various doses, frequencies, and release rates.

Evaluate Dynamics of IL-6 Release during Step-up Dosing of Subcutaneous Administration of Odronextamab Via a Quantitative Systems Pharmacology Modeling Approach

Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, eliciting T-cell-mediated cytotoxicity independent of T-cell receptor-mediated recognition. T-cell activation following odronextamab administration can result in a transient but clinically significant increase in circulating cytokine concentrations. This may lead to cytokine release syndrome (CRS), one of the most important safety concerns with T-cell engaging therapies. As most cytokine release occurs during the early weeks of treatment, a step-up dosing strategy prior to administration of a full treatment dose appears to be a successful strategy to mitigate the level of cytokine release and attenuate the occurrence of CRS. This study was performed to evaluate interleukin (IL)-6 profiles following odronextamab subcutaneous (SC) injection during Cycle 1 step-up dosing (Weeks 1-3) in patients with B-cell non-Hodgkin lymphoma (B-NHL). A quantitative systems pharmacology (QSP) model, which is an emerging mathematical modeling approach that can help improve our understanding of drug-disease interactions and can be used to evaluate hypothetical scenarios in preclinical and clinical settings, was developed and applied to identify SC step-up doses of odronextamab suitable for investigating in clinical studies. Methods A QSP model that can describe IL-6 profiles (a surrogate cytokine associated with CRS) following intravenous (IV) odronextamab was previously developed and calibrated using pharmacodynamic data from the Phase I ELM-1 study (NCT02290951; Toroghi MK. ACoP11 2020. Poster TUE-054). The IV QSP model was updated by adding relevant components (e.g. drug absorption compartment, lymph node compartment) to enable the description of IL-6 profiles following SC administration of odronextamab. Model parameters were calibrated using IL-6 concentration data of other CD20×CD3 bispecific antibodies under SC administration reported in the literature (Matasar M. ASH 2020. Poster 2096). Odronextamab SC step-up doses of interest were proposed and IL-6 profiles of these regimens were simulated with the SC QSP model. In each dosing scenario, IL-6 profiles were simulated in 300 virtual patients. The cytokine release criterion for regimen selection was that the peak IL-6 concentrations of a SC step-up regimen should be lower than peak IL-6 concentrations observed with the previously tested IV regimens. Results Simulation results indicated that the predicted IL-6 profiles were similar with or without split dosing; the former was effectively used in the IV regimen for management of CRS. The predicted highest peak IL-6 value in Week 1 with SC dose of 2 mg was considerably lower than that of IV dosing of 0.7 mg (split 0.2 mg and 0.5 mg over 2 days in Week 1). The predicted highest IL-6 concentration with 2 mg SC was 150 pg/mL and that for 0.7 mg IV was 2,100 pg/mL, indicating a reduction of more than 90%. The predicted IL-6 profiles in Week 4 were similar with 160 mg IV or 400 mg SC doses. Based on the comparison of IL-6 profiles of multiple SC dosing scenarios, SC step-up doses of 2 mg in Week 1, 26 mg in Week 2, and 100 mg in Week 3 were selected, followed by a full dose of 400 mg. The proposed SC regimen is being tested in the clinical study ELM-1 for safety and efficacy evaluations. Conclusion The QSP modeling supported the selection of the odronextamab SC step-up dosing regimen to be evaluated in a clinical study in patients with B-NHL. The selected step-up regimen for SC odronextamab allows adequate step-up to effective therapeutic doses while simplifying and improving overall convenience. The simulations suggest that no split dosing is necessary for SC administration, which may further reduce overall hospital resource burden and requirements for in-patient monitoring.