A PK–PD Model for Predicting the Impact of Age, CYP2C9, and VKORC1 Genotype on Individualization of Warfarin Therapy

Hamberg, Ak; Ml, Dahl; Barban, M; Scordo, Maria Gabriella; Wadelius, Mia; Pengo, Vittorio; Padrini, Roberto; Jonsson, E. Niclas

doi:10.1038/sj.clpt.6100084

Cited by 130 publications

(142 citation statements)

References 25 publications

(55 reference statements)

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“…Therefore, an indirect response model with a chain of transit compartments, as described previously [23,24] , was applied for the transduction of the DEX exposure to the mRNA response. In the absence of the drug, it was assumed that CYP3A1 and CYP3A2 mRNA were produced from their DNA according to a zero-order rate constant, k in , and degraded according to a first-order rate constant, k out .…”

Section: Cyp3a1 and Cyp3a2 Mrna Dynamicsmentioning

confidence: 99%

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

Deng

et al. 2012

Acta Pharmacol Sin

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Aim: To develop a pharmacokinetic/pharmacodynamic (PK/PD) model describing the receptor/gene-mediated induction of CYP3A1/2 by dexamethasone (DEX) in rats. Methods: A group of male Sprague-Dawley rats receiving DEX (100 mg/kg, ip) were sacrificed at various time points up to 60 h posttreatment. Their blood sample and liver were collected. The plasma concentration of DEX was determined with a reverse phase HPLC method. CYP3A1/2 mRNA, protein levels and enzyme activity were measured using RT-PCR, ELISA and the testosterone substrate assay, respectively. Data analyses were performed using a first-order conditional estimate (FOCE) with INTERACTION method in NON-MEM version 7.1.2. Results: A two-compartment model with zero-order absorption was applied to describe the pharmacokinetic characteristics of DEX. Systemic clearance, the apparent volume of distribution and the duration of zero-order absorption were calculated to be 172.7 mL·kg --1 ·h -1 , 657.4 mL/kg and 10.47 h, respectively. An indirect response model with a series of transit compartments was developed to describe the induction of CYP3A1/2 via PXR transactivation by DEX. The maximum induction of CYP3A1 and CYP3A2 mRNA levels was achieved, showing nearly 21.29-and 8.67-fold increases relative to the basal levels, respectively. The CYP3A1 and CYP3A2 protein levels were increased by 8.02-fold and 2.49-fold, respectively. The total enzyme activities of CYP3A1/2 were shown to increase by up to 2.79-fold, with a lag time of 40 h from the Tmax of the DEX plasma concentration. The final PK/PD model was able to recapitulate the delayed induction of CYP3A1/2 mRNA, protein and enzyme activity by DEX. Conclusion: A mechanism-based PK/PD model was developed to characterize the complex concentration-induction response relationship between DEX and CYP3A1/2 and to resolve the drug-and system-specific PK/PD parameters for the course of induction.

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Section: Cyp3a1 and Cyp3a2 Mrna Dynamicsmentioning

confidence: 99%

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

Deng

et al. 2012

Acta Pharmacol Sin

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“…TM208 demonstrated a similar efficacy (k TM208 of 0.349 cm 3 /week) to the published estimates of the antitumor effects of other EGFR inhibitors, such as erlotinib (0.507 cm 3 /week) [13] . The transit compartment model has often been used to characterize the delayed effects of pharmacodynamic responses in the signal transduction process [10,39] . In this study, the model was used to describe the delay in PD, which is driven by drug exposure.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice

et al. 2016

Acta Pharmacol Sin

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Aim:The novel anticancer compound TM208 is an EGFR tyrosine kinase inhibitor (EGFR-TKI). Since the development of resistance to EGFR-TKIs is a major challenge in their clinical usage, we investigated the profiles of resistance following continuous treatment with TM208 in human breast cancer xenograft mice, and identified the relationship between the tumor pEGFR levels and tumor growth inhibition. Methods: Female BALB/c nude mice were implanted with human breast cancer MCF-7 cells, and the xenograft mice received TM208 (50 or 150 mg·kg -1 ·d -1 , ig) or vehicle for 18 d. The pharmacokinetics (PK) and pharmacodynamics (PD) of TM208 were evaluated. Results: The PK properties of TM208 were described by a one-compartment model with first-order absorption kinetics. Our study showed the inhibitory effects of TM208 on tumor pEGFR levels gradually reached a maximum effect, after which it became weaker over time, which was characterized by a combined tolerance/indirect response PD model with an estimated EC 50 (55.9 μg/L), as well as three parameters ('a' of 27.2%, 'b' of 2730%, 'c' of 0.58 h -1 ) denoting the maximum, extent and rate of resistance, respectively. The relationship between the tumor pEGFR levels and tumor growth inhibition was characterized by a combined logistic tumor growth/ transit compartment model with estimated parameters associated with tumor growth characteristics k ng (0.282 day -1 ), drug potency k TM208 (0.0499 cm 3 /day) and the kinetics of tumor cell death k 1 (0.141 day -1 ), which provided insight into drug mechanisms and behaviors. Conclusion: The proposed PK/PD model provides a better understanding of the pharmacological properties of TM208 in the treatment of breast cancer. Furthermore, simulation based on a tolerance model allows prediction of the occurrence of resistance.

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“…15 The adult model was based on published research of the concentration-effect relationship for warfarin as well as data from the adult warfarin CROWN (CReating an Optimal Warfarin dosing Nomogram) trial. 5,16 The model was developed using data from an initial 271 subjects and subsequently validated in the same trial by using model-derived dosage in 117 subjects.…”

Section: Prior Adult Modelmentioning

confidence: 99%

“…Polymorphisms in two genes, cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase C1 (VKORC1), are involved in the pharmacokinetic (PK) and pharmacodynamics (PD) of warfarin, respectively, and variant alleles have been shown to result in increased international normalized ratio (INRs) and reduced warfarin dose requirements. [1][2][3][4][5][6][7] The CYP2C9 variant alleles *2 and *3 reportedly reduce warfarin clearance to approximately 30% and 15% of normal, respectively. 1,5 Patients with these variant alleles also tend to achieve a stable dosage regimen later and are at a significantly increased risk of bleeding compared with patients with the CYP2C9*1*1 (homozygous wildtype) genotype.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7] The CYP2C9 variant alleles *2 and *3 reportedly reduce warfarin clearance to approximately 30% and 15% of normal, respectively. 1,5 Patients with these variant alleles also tend to achieve a stable dosage regimen later and are at a significantly increased risk of bleeding compared with patients with the CYP2C9*1*1 (homozygous wildtype) genotype. 3 Multiple polymorphisms in the VKORC1 gene, such as the rs9923231 (-1639 G>A) and the rs9934438 (1173C>T) sites, occur in linkage disequilibrium and have been shown to increase warfarin sensitivity by 30% to 50%.…”

Section: Introductionmentioning

confidence: 99%

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Genetics-Based Pediatric Warfarin Dosage Regimen Derived Using Pharmacometric Bridging

Lala

Burckart

Takao

et al. 2013

The Journal of Pediatric Pharmacology and Therapeutics

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BACKGROUND Warfarin dosage regimens using CYP2C9 and VKORC1 polymorphisms have been extensively studied in adults and is included in US Food and Drug Administration-approved warfarin labeling. However, no dosage algorithm is available for pediatric patients. OBJECTIVES To derive a genetics-based pediatric dosge regimen for warfarin, including starting dose and titration scheme. METHODS A model-based approach was developed based on a previously validated warfarin dosage model in adults, with subsequent comparison to pediatric data from pediatric warfarin dose, genotyping, and international normalized ratio (INR) results. The adult model was based on a previously established model from the CROWN (CReating an Optimal Warfarin dosing Nomogram) trial. Pediatric warfarin data were obtained from a study conducted at the Children's Hospital of Los Angeles with 26 subjects. Variant alleles of CYP2C9 (rs1799853 or *2, and rs1057910 or *3) and the VKORC1 single nucleotide polymorphism (SNP) rs9923231 (-1639 G>A) were assessed, where the rs numbers are reference SNP identification tags assigned by the National Center for Biotechnology Information. RESULTS A pediatric warfarin model was derived using the previously validated model and clinical pharmacology considerations. The model was validated, and clinical trial simulation and stochastic modeling were used to optimize pediatric dosage and titration. The final dosage regimen was optimized based on simulations targeting a high (≥60%) proportion of INRs within the therapeutic range by week 2 of warfarin therapy while minimizing INRs >3.5 or <2. CONCLUSIONS The proposed pediatric warfarin dosage scheme based on individual CYP2C9 (alleles *1,*2,*3) and VKORC1 rs9923231 (-1639 G>A) genotypes may offer improved dosage compared to current treatment strategies, especially in patients with variant CYP2C9 and VKORC1 alleles. This pilot study provides the foundation for a larger prospective evaluation of genetics-based warfarin dosage in pediatric patients. INDEx TERMS

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A PK–PD Model for Predicting the Impact of Age, CYP2C9, and VKORC1 Genotype on Individualization of Warfarin Therapy

Cited by 130 publications

References 25 publications

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice

Genetics-Based Pediatric Warfarin Dosage Regimen Derived Using Pharmacometric Bridging

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