Exploration of sexual dimorphism and inter-individual variability in multivariate parameter spaces for a pharmacokinetic compartment model

The paper considers a point of view, based on the conception of the broad understanding of taxons. According to this point of view, rhyncholites of the subgenus Dentatobeccus and Microbeccus are accepted to be synonymous with the genus Rhynchoteuthis, and subgenus Romanovichella is considered to be synonymous with the genus Palaeoteuthis. The criteria, exercising influence on the different approaches to the classification of rhyncholites, have been analyzed (such as age and individual variability, sexual dimorphism, pathological and teratological features, degree of disintegration of material), underestimation of which can lead to inaccuracy. Divestment of the subgenuses Dentatobeccus, Microbeccus and Romanovichella, possessing very bright morphological characteristics, to have an independent status and denomination to their synonyms, has been noted to be unjustified. An artificial system (any suggested variant) with all its minuses is a single probable system for rhyncholites. The main criteria, minimizing its negative sides and proving the separation of the new taxon, is an available mass-scale material. The narrow understanding of the genus, used in sensible limits, has been underlined to simplify the problem of the passing the view about the genus to the other investigators and recognition of rhyncholites for the practical tasks.

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Population Pharmacokinetics of Recombinant Factor VIIa in Volunteers Anticoagulated with Acenocoumarol

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615148 ◽

1998 ◽

Vol 80 (07) ◽

pp. 109-113 ◽

Cited By ~ 30

Author(s):

Patrice Nony ◽

Elisabeth Erhardtsen ◽

Sylvie Delair ◽

Patrick Ffrench ◽

Marc Dechavanne ◽

...

Keyword(s):

Factor Viia ◽

Compartment Model ◽

Volume Of Distribution ◽

Individual Variability ◽

Factor Vii ◽

Recombinant Activated Factor Vii ◽

Activated Factor Vii ◽

Dose Ranging ◽

Endogenous Activity ◽

Dose Dependent

SummaryThis study establishes a population PK model for FVII clotting activity (FVII:C) after injection of recombinant activated factor VII (rFVIIa) to healthy volunteers. Twenty eight volunteers, anticoagulated with acenocoumarol, received one or two rFVIIa injections, with dose ranging from 5 to 320 μg/kg. The FVII:C kinetic was fitted to a 2 compartment model, with continuous “endogenous perfusion” mimicking endogenous activity. Estimated clearance was 2.4 l/h (20% inter-individual variability and 9% inter-period variability). The volume of distribution at steady-state appeared to be significantly dose dependent: 78 ml/kg for doses ≤20 μg/kg and 88 ml/kg for doses >20 μg/kg respectively, with 16% inter-individual variability. The dose producing 50% of the maximum drop of INR was estimated to be 2.2 μg/kg. The model will be used to better define the dosage regimen for future clinical developments.

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Population pharmacokinetics of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.2545 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 2545-2545

Author(s):

H. Wu ◽

R. K. Ramanathan ◽

S. Srychor ◽

B. A. Zamboni ◽

S. Ramalingam ◽

...

Keyword(s):

Body Weight ◽

Solid Tumors ◽

Topoisomerase I ◽

Plasma Concentrations ◽

Ideal Body Weight ◽

Compartment Model ◽

Individual Variability ◽

Synthetic Analogue ◽

Population Pk ◽

Linear And Nonlinear

2545 Background: CKD-602, a semi-synthetic analogue of campothecin, is a potent topoisomerase I inhibitor. S-CKD602, a PEGylated long-circulating liposomal formulation of CKD-602, was developed to achieve a longer intra-tumoral exposure of CKD602 and a higher therapeutic index. Age and body composition were reported to affect the pharmacokinetics (PK) of S- CKD602 (Zamboni, ASCO'07). A population PK model for encapsulated and released CKD-602 following administration of S- CKD602 was developed to assess factors that may influence S-CKD602 PK. Methods: Plasma samples from 45 patients (pts) with solid tumors were collected in a phase I study. S-CKD602 was administered as a 1 h IV infusion with doses ranging from 0.1 to 2.5 mg/m2. Plasma concentrations of encapsulated (n=292) and released (n=268) CKD-602 were measured by LC-MS/MS, and population PK modeling was performed using NONMEM. Results: Pts were classified as linear and nonlinear pts according to the clearance (CL) of encapsulated CKD-602 using a classic two stage PK modeling approach. Mean ± SD ratio of total body weight to ideal body weight of pts with linear and nonlinear CL of encapsulated CKD-602 was 1.13 ± 0.16 and 1.53 ± 0.29, respectively (P = 0.003). PK of encapsulated CKD-602 was described by 1-compartment model with nonlinear CL (Michaelis-Menten kinetics). PK of released CKD-602 was described by a 2- compartment model with linear CL for all pts. The presence of primary or metastatic tumor(s) located in the liver decreased the inter- individual variability (IIV) in the CL of encapsulated CKD-602 by 13%. Typical values of Vmax of encapsulated CKD-602 in pts with and without hepatic tumor(s) were 156 and 103 μg/h, respectively (P < 0.001). The inclusion of age decreased IIV in the release of CKD-602 from S-CKD602 by 22%. Typical values of release of CKD-602 from S-CKD602 in pts < 60 years old (yo) and pts ≥ 60 yo were 0.21 and 0.10 L/h, respectively (P < 0.001). Conclusions: These data suggest that older patients (pts ≥ 60 yo) have a reduced release of CKD-602 from S-CKD602. In addition, pts with tumors in the liver may have an increased clearance of S-CKD602. These observations have potential implications in the optimal dosing of liposomal agents. [Table: see text]

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Human pharmacokinetic (PK) characterization of the novel dual-action anti-HER3/EGFR antibody MEHD7945A (MEHD) in patients with refractory/recurrent epithelial tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2567 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2567-2567 ◽

Cited By ~ 1

Author(s):

Manuel Hidalgo ◽

Antonio Calles ◽

Dejan Juric ◽

Rodrigo Dienstmann ◽

Desamparados Roda Perez ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Population Analysis ◽

Demographic Data ◽

Single Agent ◽

Compartment Model ◽

Individual Variability ◽

Study Patient ◽

Epithelial Tumors ◽

Dual Action

2567 Background: MEHD is a novel dual-action human IgG1 antibody that blocks ligand binding to HER3 and EGFR, and elicits antibody-dependent cell-mediated cytotoxicity (ADCC). MEHD demonstrates single-agent activity in a broad panel of tumor models, including models resistant to anti-HER3 or anti-EGFR treatment alone. The objective of this analysis was to characterize the PK of MEHD associated with body weight (BW)-based dosing used in a phase I study in patients with epithelial tumors and to evaluate the potential for using fixed dosing in future studies. Methods: Preliminary non-compartmental and population PK analyses were performed using patient data from the dose-escalation stage [1, 4, 10, 15, 22, and 30 mg/kg every two weeks (q2w)] and expansion stage (14 mg/kg q2w) of the phase I study. Patient demographic data and other relevant clinical covariates were evaluated in the population analysis. PK simulation of 1000 subjects with a log-normal BW distribution was performed to compare the inter-individual variability of MEHD exposure following fixed or BW-based dosing. Results: As expected,MEHD exhibited nonlinear PK. In the noncompartmenal analysis, the apparent clearance (CL) decreased in a dose-dependent fashion (about 40 to 9.9 mL/day/kg from 1 to 30 mg/kg) and approached linearity at doses >10 mg/kg (q2w). In the population analysis, the PK profile of MEHD was well described by a two compartment model with linear and nonlinear clearance. The target-mediated clearance was consistent with that of anti-EGFR antibodies. The nonspecific CL and central volume of distribution (V1) values were approximately 6 mL/day/kg and 52.4 mL/kg, respectively. BW had a moderate effect on V1, but not on CL. PK simulations suggest that, compared with BW-based dosing, fixed dosing would result in less inter-individual variability in MEHD exposure. Both 1100 mg q2w or 1650 mg q3w of MEHD achieve the targeted therapeutic exposure. Conclusions: The dual-action antibody MEHD demonstrated PK consistent with anti-EGFR antibodies. Fixed dosing of MEHD on an every 2 or 3 week schedule is supported.

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Population pharmacokinetics of daptomycin in patients with bone and joint infection: minimal effect of rifampicin co-administration and confirmation of a sex difference

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkab006 ◽

2021 ◽

Author(s):

Romain Garreau ◽

Romain Bricca ◽

Marie-Claude Gagnieu ◽

Sandrine Roux ◽

Anne Conrad ◽

...

Keyword(s):

Joint Infection ◽

Compartment Model ◽

Volume Of Distribution ◽

Individual Variability ◽

Therapeutic Drug ◽

Marginal Effect ◽

Bone And Joint Infection ◽

Two Compartment Model ◽

Central Volume ◽

Trough Concentrations

Abstract Background Daptomycin is increasingly used in the treatment of bone and joint infection (BJI), but its pharmacokinetics (PK) and dosage requirements have not been thoroughly investigated in this indication. Daptomycin may be co-administered with rifampicin, which raises questions about a potential drug interaction. Objectives To investigate the population PK and dosage requirements of daptomycin in patients with BJI, and examine the influence of rifampicin co-administration. Methods A population approach was used to analyse PK data from patients who received daptomycin in our regional reference for BJI. We examined the influence of available covariates, including rifampicin co-administration on daptomycin PK. Simulations performed with the final model investigated the influence of dosages and covariates on PTA for both efficacy and safety. Results A total of 1303 daptomycin concentrations from 183 patients were analysed. A two-compartment model best described the data. Significant intra-individual variability was observed. Daptomycin clearance was influenced by renal function and sex, with females having a 26% lower typical clearance than males. Central volume of distribution (V1) was influenced by body weight, age, sex and rifampicin co-administration. Typical V1 was 11% lower in patients who were co-administered rifampicin. In PK/PD simulations, sex influenced the probability of AUC24/MIC target attainment, while rifampicin had a marginal effect. Conclusions A daptomycin dosage of 8 mg/kg/24 h in women and 10 mg/kg/24 h in men should optimize efficacy but may lead to excessive trough concentrations in many patients, especially in women. Therapeutic drug monitoring appears necessary for precision dosing of daptomycin.

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Semi-Mechanism-Based Pharmacokinetic-Toxicodynamic Model of Oxaliplatin-Induced Acute and Chronic Neuropathy

Pharmaceutics ◽

10.3390/pharmaceutics12020125 ◽

2020 ◽

Vol 12 (2) ◽

pp. 125 ◽

Cited By ~ 1

Author(s):

Shinji Kobuchi ◽

Risa Shimizu ◽

Yukako Ito

Keyword(s):

Peripheral Neuropathy ◽

Time Course ◽

Compartment Model ◽

Threshold Value ◽

Individual Variability ◽

Indirect Response Model ◽

Anticancer Efficacy ◽

Indirect Response ◽

Transit Compartment ◽

Optimal Dosing

Oxaliplatin (L-OHP) is widely prescribed for treating gastroenterological cancer. L-OHP-induced peripheral neuropathy is a critical toxic effect that limits the dosage of L-OHP. An ideal chemotherapeutic strategy that does not result in severe peripheral neuropathy but confers high anticancer efficacy has not been established. To establish an optimal evidence-based dosing regimen, a pharmacokinetic-toxicodynamic (PK-TD) model that can characterize the relationship between drug administration regimen and L-OHP-induced peripheral neuropathy is required. We developed a PK-TD model of L-OHP for peripheral neuropathy using Phoenix® NLME™ Version 8.1. Plasma concentration of L-OHP, the number of withdrawal responses in the acetone test, and the threshold value in the von Frey test following 3, 5, or 8 mg/kg L-OHP administration were used. The PK-TD model consisting of an indirect response model and a transit compartment model adequately described and simulated time-course alterations of onset and grade of L-OHP-induced cold and mechanical allodynia. The results of model analysis suggested that individual fluctuation of plasma L-OHP concentration might be a more important factor for individual variability of neuropathy than cell sensitivity to L-OHP. The current PK-TD model might contribute to investigation and establishment of an optimal dosing strategy that can reduce L-OHP-induced neuropathy.

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Population pharmacokinetics of fondaparinux administered at prophylactic doses after major orthopaedic surgery in everyday practice

Thrombosis and Haemostasis ◽

10.1160/th10-02-0127 ◽

2010 ◽

Vol 104 (08) ◽

pp. 252-260 ◽

Cited By ~ 13

Author(s):

Paul Zufferey ◽

Denis Baylot ◽

Philippe Nguyen ◽

Jeanne-Yvonne Borg ◽

Michaela Fontenay ◽

...

Keyword(s):

Body Weight ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Drug Exposure ◽

Compartment Model ◽

Individual Variability ◽

Everyday Practice ◽

Population Pharmacokinetic ◽

Antithrombotic Agent ◽

Orthopaedic Patients

SummaryFondaparinux is a synthetic antithrombotic agent with specific anti-factor Xa activity. A population pharmacokinetic model of fondaparinux, based on data obtained in patients included in phase II/III trials, has been described. However, the validity of this model in everyday practice needed to be confirmed. This study was a multicenter, prospective cohort study in consecutive orthopaedic patients treated with 2.5 mg of fondaparinux. Anti-Xa activities were recorded in 809 patients. Population parameters and inter-individual variability were estimated using NONMEM VI software. A two-compartment model with first-order absorption best described fondaparinux pharmacokinetics. Covariates partly explaining inter-individual variability were body weight, age and creatinine clearance estimated by the simplified Modification of Diet in Renal Disease formula (MDRD). A body weight less than 50 kg and moderate renal failure increased drug exposure. Although the population pharmacokinetic model of fondaparinux was described, this one requires to be validated in everyday practice.

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Clinical pharmacokinetics and dose recommendations for posaconazole gastroresistant tablets in children with cystic fibrosis

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkab312 ◽

2021 ◽

Author(s):

Siân Bentley ◽

Jane C Davies ◽

Silke Gastine ◽

Jackie Donovan ◽

Joseph F Standing

Keyword(s):

Cystic Fibrosis ◽

Model Building ◽

Compartment Model ◽

Individual Variability ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Electronic Patient Records ◽

Clinical Pharmacokinetics ◽

Dose Scheme ◽

Highly Correlated

Abstract Objectives To investigate the population pharmacokinetics of posaconazole gastroresistant tablets in children with cystic fibrosis (CF) and perform simulations to recommend optimal doses. Patients and methods Children from a paediatric CF centre who had received posaconazole tablets and underwent therapeutic drug monitoring were identified from pharmacy records. Relevant clinical data were collated from case notes and electronic patient records and used to develop an allometrically scaled population pharmacokinetic model. A stepwise covariate model-building exercise evaluated the influence of interacting medicines and liver function. Results One hundred posaconazole serum concentrations were collected from 37 children with a median age of 14 years (range 7–17). Posaconazole pharmacokinetics were adequately described by a one-compartment model with inter-individual variability on clearance. Dose simulations demonstrated a 77%–83% probability of attaining a trough target of 1 mg/L with a dose of 300 mg every 12 h for two doses then 300 mg once daily (OD) in children aged 6–11 years; and 86%–88% with a dose of 400 mg every 12 h for two doses then 400 mg OD in adolescents aged 12–17 years. This dose scheme also yielded a 90% probability of achieving an AUC of 30 mg·h/L. AUC and trough concentration were highly correlated (r2 = 0.98). Simulations showed that trough concentrations of >0.75 mg/L would exceed an AUC of 30 mg·h/L in 90% of patients. Conclusions A starting dose of 300 mg OD in those aged 6–11 years and 400 mg OD in those aged 12–17 years (following loading doses) yields a 90% probability of attaining an AUC of 30 mg·h/L.

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Independent confirmation of the strong early predictive value of modeled PSA clearance in prostate cancer patients treated by radical prostatectomy: Results of the prospective PSAMODEL study.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e15182 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e15182-e15182 ◽

Cited By ~ 3

Author(s):

Denis Maillet ◽

Alain Ruffion ◽

Paul Perrin ◽

Melanie Wilbaux ◽

Emilie Henin ◽

...

Keyword(s):

Prostate Cancer ◽

Radical Prostatectomy ◽

Predictive Value ◽

Cox Model ◽

Compartment Model ◽

Initial Study ◽

Individual Variability ◽

Rank Test ◽

Biochemical Relapse ◽

Early Predictor

e15182 Background: Early predictors of relapse after radical prostatectomy are needed. We previously showed that mathematical modeling of PSA kinetics provides a parameter, apparent PSA clearance (CLPSA), which may be a significant early predictor of biochemical relapse [1] (You et al; Prostate 2009;69:1325). Validation of these outcomes in an independent prospective study was warranted. Methods: As required by the initial study, four PSA values were prospectively measured during the first 50 days following radical prostatectomy in 119 patients with localized prostate cancer at our center. PSA values were centrally measured. The bi-compartment model previously reported in 2009 [1] was used to calculate patient CLPSA with NONMEM program. The predicted risk of biochemical relapse based on CLPSA cut-off previously defined (threshold at 0.048 [1]) was assessed using survival univariate and multivariate analyses. The primary endpoint was 3-year biochemical relapse free survival (3 y-bRFS). Results: The data from 119 patients treated with radical prostatectomy were analyzed. Among them 13 experienced a relapse after median 6.5 months. Despite large inter-individual variability, individual PSA decline profiles of patients were well fitted by the model. CLPSA categorized by the same cut-off previously described [1] was a significant predictor of 3 y-bRFS using log-rank test (97% vs 66%, p=0.009). Moreover it had independent significant predictive value when adjusted on other prognostic factors (D’Amico score) using multivariate Cox model (p<0.05). Conclusions: This prospective PSAMODEL studyconfirms modeled CLPSA calculated during the first 50 days after radical prostactectomy is a strong independent reproducible early predictor of biochemical relapse. It may easily be calculated using 4 PSA values after surgery. The potential role of this factor in adjuvant treatment adjustment may be studied. [1] You et al; Prostate 2009;69:1325

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Population pharmacokinetics (popPK) of Sym004 to evaluate the effect of intrinsic and extrinsic factors on exposure in metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.496 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 496-496

Author(s):

Lene Alifrangis ◽

Rik Schoemacker ◽

Niels Jorgen Ostergaard Skartved ◽

Rikke Hald ◽

Maria Düring ◽

...

Keyword(s):

Body Weight ◽

Compartment Model ◽

Hepatic Function ◽

Individual Variability ◽

Tumor Type ◽

Phase 3 ◽

Extrinsic Factors ◽

Poppk Model ◽

Non Linear ◽

Intrinsic And Extrinsic Factors

496 Background: Sym004 consists of two anti-EGFR monoclonal antibodies (futuximab and modotuximab) directed against non-overlapping epitopes in the EGFR domain III. Sym004 induces rapid and efficient removal of the EGFR from the cancer cell surface by triggering EGFR internalization and degradation and has shown promising efficacy in mCRC patients. Based upon a post-hoc analysis of a Phase 2 study, a Phase 3 trial in genomically selected mCRC patients is in preparation. Methods: The aim was to establish a popPK model for Sym004 in order to i) evaluate impact of covariates (intrinsic and extrinsic factors) on Sym004 exposure and ii) provide exposure metrics for a PK/PD analysis. Sym004 serum concentrations were obtained from 330 patients with mCRC (n = 247) or advanced solid tumors (studies Sym004-01, Sym004-02, Sym004-05 and Sym004-06). Sym004 (0.4-18 mg/kg) was dosed by i.v. infusion weekly or every 2nd week, or as a 9 mg/kg loading dose followed by 6 mg/kg weekly (9/6 mg/kg weekly). Non-linear mixed effects modelling was done in NONMEM v7.3.0. Covariates evaluated included body weight, age, sex, race, albumin, renal function, hepatic function, tumor type and size, ECOG and previous anti-EGFR treatments. Results: The base popPK model was a 2-compartment model with linear and non-linear Michaelis-Menten-type elimination and a priori inclusion of body weight on CL, Vmax, V1 and V2. The model captured the non-linear PK well. The final covariate model retained covariates whose point estimates were outside the range of 0.8 to 1.25 and whose 90% confidence intervals did not overlap with the null value and included only body weight and albumin. Inter-individual variability was estimated for CL, Vmax and V1 and was in the range of 18-30%. Simulations were used to assess the clinical relevance of the covariates as judged by the magnitude of the change in exposure of the Phase 3 dose regimen of 9/6 mg/kg weekly. Conclusions: The popPK model described the Sym004 PK data well. No covariates were present that changed the Sym004 exposure in a clinically significant manner which would necessitate a dose modification. The model is suitable for simulating the Sym004 PK for PK/PD analyses. Clinical trial information: NCT01117428,NCT01417936,NCT02083653,NCT01955473.

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