Two-compartment Pharmacokinetic Model Research Articles

Population pharmacokinetics of tacrolimus whole blood and peripheral blood mononuclear cell concentrations in stable kidney-transplanted patients.

Therapeutic drug monitoring of tacrolimus based on whole blood drug concentrations is routinely performed. The concentration of tacrolimus in peripheral blood mononuclear cells (PMBCs) is likely to better reflect drug exposure at the treatment target site. We aimed to describe the relationship between tacrolimus whole blood and PBMC concentrations, and the influence of patient characteristics on this relationship by developing a population pharmacokinetic model. We prospectively enrolled 63 stable adult kidney-transplanted patients and collected dense (12-h, n = 18) or sparse (4-h, n = 45) pharmacokinetic profiles of tacrolimus. PBMCs were isolated from whole blood (Ficoll density gradient centrifugation), and drug concentrations in whole blood and PBMCs were analysed using liquid chromatography-mass spectrometry. Patient genotype (CYP3A4/5, ABCB1, NR1I2) was assessed with PCR. Population pharmacokinetic modelling and statistical evaluation was performed using NONMEM. Tacrolimus whole blood concentrations were well described using a two-compartment pharmacokinetic model with a lag-time and first-order absorption and elimination. Tacrolimus PBMC concentrations were best estimated from whole blood concentrations with the use of a scaling factor, the ratio of whole blood to PBMC concentrations (RC:PBMC), which was the extent of tacrolimus distribution into PBMC. CYP3A5*1 non-expressors and NR1I2-25 385T allele expressors demonstrated higher RC:PBMC ratios of 42.4% and 60.7%, respectively. Tacrolimus PBMC concentration could not be accurately predicted from whole blood concentrations and covariates because of significant residual unexplained variability in the distribution of tacrolimus into PBMCs and may need to be measured directly if required for future studies.

Population Pharmacokinetic Analysis of Tucatinib in Healthy Participants and Patients with Breast Cancer or Colorectal Cancer.

Tucatinib is a highly selective, oral, reversible, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor. Tucatinib is approved at a 300-mg twice-daily dose in adults in combination with trastuzumab and capecitabine for advanced HER2-postitive (HER2+) unresectable or metastatic breast cancer and in combination with trastuzumab for RAS wild-type HER2+ unresectable or metastatic colorectal cancer. This study sought to characterize the pharmacokinetics (PK) and assess sources of PK variability of tucatinib in healthy volunteers and in patients with HER2+ metastatic breast or colorectal cancers. A population pharmacokinetic model was developed based on data from four healthy participant studies and three studies in patients with either HER2+ metastatic breast cancer or metastatic colorectal cancer using a nonlinear mixed-effects modeling approach. Clinically relevant covariates were evaluated to assess their impact on exposure, and overall model performance was evaluated by prediction-corrected visual predictive checks. A two-compartment pharmacokinetic model with linear elimination and first-order absorption preceded by a lag time adequately described tucatinib pharmacokinetic profiles in 151 healthy participants and 132 patients. Tumor type was identified as a significant covariate affecting tucatinib bioavailability and clearance, resulting in a 1.2-fold and 2.1-fold increase in tucatinib steady-state exposure (area under the concentration-time curve) in HER2+ metastatic colorectal cancer and HER2+ metastatic breast cancer, respectively, compared with healthy participants. No other covariates, including mild renal or hepatic impairment, had an impact on tucatinib pharmacokinetics. The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model. NCT03723395, NCT03914755, NCT03826602, NCT03043313, NCT01983501, NCT02025192.

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.

Predicting Human Subcutaneous Bioavailability of Therapeutic Monoclonal Antibodies from Systemic Clearance and Volume of Distribution.

Subcutaneous delivery of monoclonal antibody therapeutics is often preferred to intravenous delivery due to better patient compliance and overall lower cost to the healthcare system. However, the systemic absorption of biologics dosed subcutaneously is often incomplete. The aim of this work was to describe a human bioavailability prediction method for monoclonal antibodies delivered subcutaneously that utilizes intravenous pharmacokinetic parameters as input. A two-compartment pharmacokinetic model featuring a parallel-competitive absorption pathway and a presystemic metabolism pathway was employed. A training data set comprised 19 monoclonal antibodies (geometric mean bioavailability of 68%), with previously reported human pharmacokinetic parameters, while a validation set included data compiled from 5 commercial drug products (geometric mean bioavailability of 69%). A single fitted absorption rate constant, paired with compound-specific estimates of presystemic metabolism rate proportional to compound-specific systemic clearance parameters, resulted in calculations of human subcutaneous bioavailability closely mimicking clinical data in the training data set with a root-mean-square error of 5.5%. Application of the same approach to the validation data set resulted in predictions characterized by 12.6% root-mean-square error. Factors that may have impacted the prediction accuracy include a limited number of validation data set compounds and an uncertainty in the absorption rate, which were subsequently discussed. The predictive method described herein provides an initial estimate of the subcutaneous bioavailability based exclusively on pharmacokinetic parameters available from intravenous dosing.

Pharmacokinetic Profile of Ceftriaxone and Meropenem in Dogs

The principal aim of the study was evaluating the pharmacokinetic of ceftriaxone and meropenem in dogs, eight healthy male dogs were used for this experiment. A microbiological assay was used to determine the pharmacokinetic indices of ceftriaxone and meropenem given intravenously. The values were then fitted to a two-compartment pharmacokinetic open model in order to assess the factors related to distribution and excretion. The obtained results showed that the half-life, volume of distribution, and total body clearance to the samples of plasma of ceftriaxone and meropenem were recorded (0.83 h., 0.35 L/kg and 0.28 L/hr/kg), (0.86 h., 0.48 L/kg and 0.33 L/hr/kg), and the ratio of plasma protein binding were 16.67 %; 9.58 %, respectively. In conclusion, through the pharmacokinetic characteristics of meropenem and ceftriaxone in dogs, they possess an efficacious profile against K. pneumonia as same as other sensitive bacteria which were qualified to be a potential candidate to be one of the most commonly used parenterally administered antibacterial medicines in the treatment of acute bacterial cases that need to be treated quickly in veterinary therapy. However, the differences in the pharmacokinetic profile proved that the effectiveness of meropenem was more than ceftriaxone.

Evaluation of Obesity-Related Physiological Changes on Pantoprazole Clearance in Children Using a Population Pharmacokinetic Approach.

Pediatric obesity is a growing health concern, affecting millions of children worldwide. While pharmacokinetic (PK) changes in numerous commonly prescribed medications have been linked to obesity, the physiological mechanisms driving these alterations and their implications for drug dosing remain poorly understood. The objective of this study was to evaluate previously reported observations of reduced pantoprazole clearance (CL) in children with obesity, investigate obesity-related characteristics in liver physiology as explanatory causes for these observations, and evaluate the clinical relevance of obesity on drug dosing. A prospective, comparative PK study, enrolling participants 6-21 years of age, with and without obesity, was conducted to evaluate the association between obesity-related characteristics and pantoprazole CL. A nonlinear mixed-effects modeling approach was used to identify sources of interindividual variability in pantoprazole PK. Monte Carlo simulations were performed to assess pantoprazole exposure in children and evaluate the association between obesity and pantoprazole exposure. The study population consisted of 39 pediatric participants: 31% without obesity and 69% with obesity. A two-compartment PK model with covariate effects of total body weight (TBW), CYP2C19 metabolizer phenotype, and obesity status adequately described the PK data. After accounting for differences due to TBW and CYP2C19 metabolizer phenotype, obesity was associated with an estimated 18% reduction in pantoprazole CL (comparable to the reduction estimated for a CYP2C19 loss of function allele). Further research is warranted to evaluate the physiological mechanisms associated with reduced drug CL in children with increased body size and the implications for drug dosing.

Population pharmacokinetic/target engagement modelling of tozorakimab in healthy volunteers and patients with chronic obstructive pulmonary disease.

This study describes the pharmacokinetic (PK)/target engagement (TE) relationship of tozorakimab, an anti-interleukin (IL)-33 antibody, by building a mechanistic population PK/TE model using phase 1 biomarker data. The analysis included tozorakimab PK and TE in serum assessed in 60 tozorakimab-treated participants, including healthy adults and patients with mild chronic obstructive pulmonary disease. Scenarios evaluated three dose frequencies (once every 2, 4 or 6weeks) administered subcutaneously at seven doses of tozorakimab (30, 60, 90, 120, 150, 300 or 600 mg). For each dose, simulations were performed with 5000 virtual individuals to predict systemic TE. Inhibition of IL-33/soluble ST2 (sST2) complex levels at trough PK at steady state was assessed in each dosing scenario. The PK/TE modelling analyses were performed using a nonlinear mixed-effect modelling approach. The final two-compartment PK model with tozorakimab binding IL-33 in the central compartment adequately described the systemic PK and TE of tozorakimab at population and individual levels. The mean PK parameter estimates of absorption rate, central volume of distribution and clearance were 0.48 (90% confidence interval [CI]: 0.40-0.59, 1/day), 12.64 (90% CI: 8.60-18.62, L) and 0.87 (90% CI: 0.65-1.16, L/day), respectively. Consistent with the observed value, tozorakimab bioavailability was 45%. For all three dose frequencies, predicted inhibition of systemic IL-33/sST2 levels was more than 95% at doses greater than 90 mg. The PK/TE model reliably quantified the relationship between PK and systemic TE of tozorakimab, with potential utility for predicting clinical dose-response relationships and supporting clinical dose selection.

Optimal dosing regimen of caspofungin in adolescents with allogeneic haematopoietic stem cell transplantation.

The optimal dosing regimen of caspofungin in adolescents undergoing allogeneic haematopoietic stem cell transplantation against Candida spp. is unknown. The study aimed to compare body surface area (BSA)-based and fixed dosing regimens through population pharmacokinetic (PPK) analysis and to optimize dosing regimens likely to achieve therapeutic exposures. Opportunistic sampling was used to collect plasma concentrations through a prospective observational pharmacokinetic study. PPK analysis and Monte Carlo simulations (n = 1000) were performed using NONMEM. A total of 86 samples of 30 adolescents (12-17 years old) were best described by a two-compartment pharmacokinetic model. BSA is the only covariate on clearance and central volume of distribution. For Candida glabrata and Candida albicans, a standard dosing regimen could achieve at least a 90% probability of target attainment for the indicator of AUC0-24/MIC90. Dosing regimen simulations identified a BSA cut-off value of 1.3 m2, where a fixed loading dose (LD) is preferred when BSA ≥ 1.3 m2 and a BSA-based LD is preferred when BSA < 1.3 m2. For maintenance dose (MD), however, the BSA-based dose was proposed, regardless of BSA. The current maximum dosing regimen of LD 70 mg/day and MD 70 mg/day could not result in sufficient antifungal exposure for Candida parapsilosis with MIC90 of 1 mg/L. Furthermore, an LD of 70 mg/day and MD of 60 mg/m2/day rendered 90.4% steady-state trough concentration (Ctrough) over 1 mg/L in the virtual population. Our study proposed optimized dosing regimens of caspofungin based on AUC0-24/MIC90 or Ctrough, which may support further individualized treatment.

Population pharmacokinetics of tamsulosine in patients with benign prostatic hyperplasia.

The study aimed to determine the typical clearance and volume of distribution values of tamsulosin in patients with benign prostatic hyperplasia (BPH), and to identify factors with a measurable impact on the drug's elimination. This open-label, single-arm population pharmacokinetic study involved 65 adult men with BPH who had been on tamsulosin therapy for at least seven days. The steady-state serum concentrations of tamsulosin were measured using liquid chromatography-tandem quadrupole mass spectrometry. Population pharmacokinetic parameters, their variability, and influencing factors were estimated based on a two-compartment pharmacokinetic model using NONMEM software. The estimated tamsulosin clearance in BPH patients was 0.719L/h, and the steady-state volume of distribution was 32L. Neither renal nor liver function parameters had a statistically significant effect on tamsulosin clearance. However, a positive correlation was observed between hemoglobin levels and tamsulosin clearance in the BPH patient cohort. Our investigation reveals significant associations between tamsulosin pharmacokinetics and specific characteristics of patients with lower urinary tract symptoms (LUTS) due to BPH. The study highlights that tamsulosin clearance is associated with hemoglobin levels in patients with LUTS/BPH. This study underscores the importance of considering patient-specific factors when managing BPH treatment with tamsulosin, emphasizing associations rather than causative relationships.

Fentanyl dosage for preterm infants suggested by a pharmacokinetic, -dynamic, and -genetic model.

Fentanyl is commonly administered for procedural pain management in preterm infants, but target concentrations have not yet been defined. To investigate pharmacokinetics (PK), -dynamics (PD), and -genetics (PG), 25 infants (gestational age 23.3-34.1 weeks) received a fentanyl dose before a skin-breaking procedure (0.5 µg/kg) or tracheal intubation (2 µg/kg). Four pain scales were used as a PD endpoint to evaluate efficacy. The impact of polymorphism in genes encoding enzymes (UGT2B7, CYP3A7, CYP3A4, COMT, CYP2D6, KCNJ6), transporters (SLC22A1, ABCC1, ABCC3) and receptor (OPRM1) on PK parameters was explored. A two-compartment PK model adequately described the fentanyl concentration. The effects of weight and maturity on the clearance were included as covariates in the model. One genetic variant encoding the ABCC1 transporter (rs111517339 T/TA) and two encoding the ABCC3 transporter (rs11079921 T/C and rs8077268 C/T) had a significant effect on fentanyl elimination that explained 15% of the interindividual variability on the clearance. A proportional odds PK/PD model was used to describe the concentration-effect relationship of fentanyl using the Échelle de douleur et d'inconfort du nouveau-né (EDIN) pain score. The simulations suggest that an intravenous dose of 2 µg/kg would be appropriate in preterm infants for a clearly painful procedure, such as an intubation. Design of personalized analgesia with fentanyl for newborn infants should consider maturation and genetic variants of opioid transporters affecting drug elimination. The results indicate that an intravenous dose of 2 μg/kg fentanyl would be suitable before a clearly painful procedure in preterm infants. Genetic variants encoding ABCC1 and ABCC3 transporters increase the clearance of fentanyl, which is a novel finding.

GFR measurement in patients with CKD: Performance and feasibility of simplified iohexol plasma clearance techniques.

Implementing shortened one-compartment iohexol plasma clearance models for GFR measurement is crucial since the gold standard inulin renal clearance technique and the reference two-compartment, 10-hour, 16-samplings iohexol plasma clearance method are clinically unfeasible. Inulin may precipitate anaphylactic shock. Four-hour and 8-hour one-compartment iohexol plasma clearance models with Bröchner-Mortensen correction provide accurate GFR measurements in patients with estimated GFR (eGFR) > or ≤40 mL/min/1.73m2, respectively. We compared the performance of the simplified 5-hour, 4-samplings, two-compartment population pharmacokinetic model (popPK) with the performance of the reference two-compartment 10-hour iohexol method in 16 patients with GFR 15.2 to 56.5 mL/min/1.73 m2. We also compared the performance of shortened (5, 6 and 7-hour) one-compartment models with the performance of the standard 8-hour one-compartment model in 101 patients with eGFR ≤40 mL/min/1.73 m2. The performance of popPK and shortened methods versus reference methods was evaluated by total deviation index (TDI), concordance correlation coefficient (CCC) and coverage probability (CP). TDI <10%, CCC ≥0.9 and CP >90% indicated adequate performance. TDI, CCC and CP of popPK were 11.11%, 0.809 and 54.10%, respectively. All shortened, one-compartment models overestimated the GFR (p <0.0001 for all) as compared to the 8-hour model. TDI, CCC and CP were 7.02%, 0.815, and 75.80% for the 7-hour model, 7.26%, 0.803, and 74.20% for the 6-hour model, and 8.85%, 0.729 and 64.70% for the 5-hour model. The agreement of popPK model was comparable to that obtained with the Chronic-Kidney-Disease-Collaboration-Epidemiology (CKD-Epi) and the Modification-of-Diet-in-Renal-Disease (MDRD) serum-creatinine based equations for GFR estimation. PopPK model is remarkably unreliable for GFR measurement in stage III-IV CKD patients. In patients with eGFR ≤40 mL/min/1.73m2, shortened one-compartment models, in particular the 5-hour model, are less performant than the reference 8-hour model. For accurate GFR measurements, the iohexol plasma clearance should be measured with appropriate protocols. Over-simplified procedures should be avoided.

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

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

Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of SAR439459, a TGFβ inhibitor, as monotherapy and in combination with cemiplimab in patients with advanced solid tumors: Findings from a phase 1/1b study.

SAR439459 (SAR'459), a "second-generation" human anti-transforming growth factor beta (TGFβ) monoclonal antibody, enhances the activity of immune checkpoint inhibitors. In this phase I/Ib study, we evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of SAR'459 ± cemiplimab (intravenous) in patients with advanced solid tumors. Increasing doses of SAR'459 were administered every 2 or 3 weeks (Q2W, Q3W) alone (Part 1A) or with 3 mg/kg cemiplimab Q2W or 350 mg Q3W (Part 1B). In Part 2A (dose expansion), melanoma patients were randomly (1:1) administered 22.5 or 7.5 mg/kg SAR'459. In Part 2B (dose expansion), 22.5 mg/kg SAR'459 and 350 mg cemiplimab Q3W were administered. The primary end points were maximum tolerated dose (MTD) or maximum administered dose (MAD; Part 1), preliminary antitumor activity (Part 2B), and optimal monotherapy dose (Part 2A). Twenty-eight and 24 patients were treated in Parts 1A and 1B, respectively; MTD was not reached, MAD was 15 (Q2W) and 22.5 mg/kg (Q3W) alone and in combination, respectively. Fourteen and 95 patients, including 14 hepatocellular carcinoma (HCC) patients, were treated in Parts 2A and 2B, respectively. The population PK model yielded satisfactory goodness-of-fit plots and adequately described the observed data by a two-compartment PK model with linear elimination. Objective responses were not observed in Parts 1 and 2A. In Part 2B, objective response rate was 8.4% and 7.1% across tumor types and the HCC cohort, respectively. The most frequent treatment-emergent adverse effects were hemorrhagic events (43.5%), keratoacanthoma (6.8%), and skin neoplasms (6.2%). Fatal bleeding occurred in 21.4% HCC patients despite the implementation of mitigation measures. SAR'459 monotherapy and combination with cemiplimab appeared relatively safe and tolerable in limited number of patients in dose escalation. However, the study was discontinued due to the unclear efficacy of SAR'459 and bleeding risk, particularly in HCC patients.

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

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

Renal Replacement Therapy as a New Indicator of Voriconazole Clearance in a Population Pharmacokinetic Analysis of Critically Ill Patients.

The pharmacokinetic (PK) profiles of voriconazole in intensive care unit (ICU) patients differ from that in other patients. We aimed to develop a population pharmacokinetic (PopPK) model to evaluate the effects of using extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and those of various biological covariates on the voriconazole PK profile. Modeling analyses of the PK parameters were conducted using the nonlinear mixed-effects modeling method (NONMEM) with a two-compartment model. Monte Carlo simulations (MCSs) were performed to observe the probability of target attainment (PTA) when receiving CRRT or not under different dosage regimens, different stratifications of quick C-reactive protein (qCRP), and different minimum inhibitory concentration (MIC) ranges. A total of 408 critically ill patients with 746 voriconazole concentration-time data points were included in this study. A two-compartment population PK model with qCRP, CRRT, creatinine clearance rate (CLCR), platelets (PLT), and prothrombin time (PT) as fixed effects was developed using the NONMEM. We found that qCRP, CRRT, CLCR, PLT, and PT affected the voriconazole clearance. The most commonly used clinical regimen of 200 mg q12h was sufficient for the most common sensitive pathogens (MIC ≤ 0.25 mg/L), regardless of whether CRRT was performed and the level of qCRP. When the MIC was 0.5 mg/L, 200 mg q12h was insufficient only when the qCRP was <40 mg/L and CRRT was performed. When the MIC was ≥2 mg/L, a dose of 300 mg q12h could not achieve ≥ 90% PTA, necessitating the evaluation of a higher dose.

Population pharmacokinetics of intravenous daptomycin in critically ill patients: implications for selection of dosage regimens.

Daptomycin is gaining prominence for the treatment of methicillin-resistant Staphylococcus aureus infections. However, the dosage selection for daptomycin in critically ill patients remains uncertain, especially in Chinese patients. This study aimed to establish the population pharmacokinetics of daptomycin in critically ill patients, optimize clinical administration plans, and recommend appropriate dosage for critically ill patients in China. The study included 64 critically ill patients. Blood samples were collected at the designated times. The blood daptomycin concentration was determined using validated liquid chromatography-tandem mass spectrometry. A nonlinear mixed-effects model was applied for the population pharmacokinetic analysis and Monte Carlo simulations of daptomycin. The results showed a two-compartment population pharmacokinetic model of daptomycin in critically ill adult Han Chinese patients. Monte Carlo simulations revealed that a daily dose of 400mg of daptomycin was insufficient for the majority of critically ill adult patients to achieve the anti-infective target. For critically ill adult patients with normal renal function (creatinine clearance rate >90mL/min), the probability of achieving the target only reached 90% when the daily dose was increased to 700mg. For patients undergoing continuous renal replacement therapy (CRRT), 24h administration of 500mg met the pharmacodynamic goals and did not exceed the safety threshold in most patients. Therefore, considering its efficacy and safety, intravenous daptomycin doses are best scaled according to creatinine clearance, and an increased dose is recommended for critically ill patients with hyperrenalism. For patients receiving CRRT, medication is recommended at 24h intervals.

Identifiability methods for biological systems: Determining subsets of parameters through sensitivity analysis, penalty-based optimisation, profile likelihood and LASSO model reduction

Parameter estimation for model equations of biological systems can be complicated when some of the parameters are not identifiable. For example this can occur if parameters are very insensitive or if there are correlations between the parameters such that ranges of different parameter values give the same model output. To solve these issues, a logical procedure is suggested which incorporates sensitivity analysis and existing methods for testing for identifiability together with a LASSO based model reduction method for obtaining potential correlations between parameters. This procedure aims to separate the full set of parameters into a subset of identifiable parameters, a subset of insensitive parameters and provide correlations for determining values of non-identifiable parameters. The combined methodology is illustrated through two case studies: A simple two-compartment pharmacokinetic model and a complex kinetic model for the bioproduction of succinic acid from glycerol.

Population pharmacokinetics of lumefantrine and its metabolite, desbutyl-lumefantrine, in children under five years of age with malaria

We developed a population pharmacokinetic model to characterize the Pharmacokinetics (PK) of lumefantrine and its active metabolite, desbutyl-lumefantrine, in children under 5 years. Data were available from 55 children treated for uncomplicated falciparum malaria with standard 3-day Artemether- Lumefantrine (AL) regimen. Combined sparse and intense PK sampling strategy was used to obtain venous samples for 28 days. Using NONMEM, a two-compartment linear pharmacokinetic model incorporating lag time with first order absorption characterized the PK of lumefantrine. Desbutyl-lumefantrine PK was also characterized with a two compartment model. Inter-subject variability in apparent Clearance (CL/F) was explained by Body Mass Index (BMI) and age, while weight partially explained variability in apparent volume of distribution of the central compartment (V2/F). Ontogeny in CYP3A4, the isozyme metabolizing lumefantrine, was incorporated into the age component of lumefantrine CL/F model. Incorporation of BMI into CL/F model explained variability due to weight and stunting. For lumefantrine typical inter-compartment clearance (Q/F), CL/F, V2/F for a typical subject weighing 13.0 kg and BMI 16.62 kg/m2 , and apparent volume of distribution of peripheral compartment (V3/F) were 0.176 L/hr, 3.19 L/hr, 28.1 L, and 58.4 L, respectively. Lumefantrine CL/F was higher in children ≤2 year compared to those &gt;2 years, notably decreased with increasing BMI (-1.10) and age from two to just less than five years (CL/FAGE: -0.423 (-0.648, -0.198)). Results indicate lumefantrine CL/F is a function of age and BMI. Our findings provide structural basis for future evaluation of rational AL dosing guidelines among under five year olds.

Abstract 7182: Blood brain barrier masks effects of dosing strategy

Abstract The penetration of the blood brain barrier (BBB) presents a significant challenge in the design of drugs targeting brain tumors. The BBB desynchronizes drug concentrations between the body and brain, complicating the relationships between drug dose, effective concentration, and toxicity. In this work, we sought to understand the nature of these relationships in the context of dose schedule, in order to suggest minimally toxic and maximally effective strategies. We developed a two-compartment pharmacokinetic model to simulate the exchange of a drug between the body and the brain. Drug exchange was based on passive diffusion through the barrier and active transport into the brain as described by Michaelis-Menten kinetics. In the model, tumor cells exhibit binary resistance to the drug under a logistic growth model. The drug reduces the growth rate of the sensitive population while the resistant population suffers a small growth penalty because of the mutation conferring resistance. Strategy effectiveness was quantified in terms of survival time, the time until 95% of carrying capacity was reached, and toxicity was evaluated as the peak moving average over 18 days. Although the BBB complicates prediction of drug action, it simplifies drug impact by masking schedule effects. Our work suggests that drug concentrations in the brain increase with initial treatment until equilibrium between active transport, diffusion, and drug metabolism is reached. Fluctuations in drug concentration resulting from breaks between bolus dosing are greatly reduced in the brain relative to the body, and high frequency (daily) dosing results in a nearly constant equilibrium drug concentration. The rate at which equilibrium is reached and the drug concentration in the brain are unaffected by dosing period, as long as the average dose per day is constant. Our model suggests that the impact of dosing cycle length on survival time is negligible. Neutropenia is minimized by schedules with dosing cycle lengths that factor evenly into the 18-day neutrophil recovery period. These schedules have consistent toxicity throughout. Strategies with two, three, six, nine, and eighteen day cycles induce neutropenia least. As fluctuations in drug concentration are small at the equilibrium steady-state, effects of scheduling on drug interactions are predicted to be minimal. As drug concentration in the brain at equilibrium and latency to equilibrium are independent of dosing period, these parameters must be modulated through changes in the amount of drug dosed. The use of a loading dose may compensate for latency. Although this analysis is based on hypothetical drugs, it provides practical insights that are applicable across a wide range of systemically dosed small-molecule therapeutics. Further, the modeling framework derived here can be readily extended to guide the design of dosing schedules for real-world therapeutic interventions. Citation Format: Madison Stoddard, Andrew Chen, Lin Yuan, Debra Van Egeren, Arijit Chakravarty. Blood brain barrier masks effects of dosing strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7182.

Population pharmacokinetics, enzyme occupancy, and pharmacodynamic modeling of soticlestat in patients with developmental and epileptic encephalopathies.

Soticlestat (TAK-935) is a first-in-class, selective inhibitor of cholesterol 24-hydroxylase (CH24H) under phase III development for the treatment of the developmental and epileptic encephalopathies (DEEs), Dravet syndrome (DS), and Lennox-Gastaut syndrome (LGS). A previous model characterized the pharmacokinetics (PKs), CH24H enzyme occupancy (EO), and pharmacodynamics (PDs) of soticlestat in healthy volunteers. The present study extended this original model for patients with DEEs and investigated sources of variability. Model-based simulations were carried out to optimize dosing strategies for use in clinical trials. Data from eight phase I and II trials of healthy volunteers or patients with DEEs receiving oral soticlestat 15-1350 mg were included, encompassing 218 individuals for population PK (PopPK) analyses and 306 individuals for PK/PD analyses. Dosing strategies were identified through model-based simulations. The final mixed-effect PopPK/EO/PD model consisted of a two-compartment PK model and an effect-site compartment in the PK/EO model; soticlestat concentrations at the effect site were linked to 24S-hydroxycholesterol plasma concentrations using a semimechanistic inhibitory indirect response model. Covariates were included to account for sources of variability. Pediatric dosing strategies were developed for four body weight bands (10 to <15, 15 to <30, 30 to <45, and 45-100 kg) to account for covariate effects by body weight. The final PopPK and PK/EO/PD models accurately described PK, EO, and PD profiles of soticlestat in healthy volunteers and patients with DEEs. Covariate analyses and model-based simulations facilitated optimization of phase III trial dosing strategies for patients with DS or LGS.