Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years

Kontny, Nina E.; Würthwein, Gudrun; Boos, Joachim; Boddy, Alan V.; Krischke, Miriam; Fuhr, Uwe; Thompson, Patrick A.; Jörger, Markus; Schellens, Jan H.M.; Hempel, Georg

doi:10.1007/s00280-013-2069-1

Cited by 38 publications

(60 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An initial population pharmacokinetic model for doxorubicin and doxorubicinol in children was set up from datasets of three earlier studies (two adults and one child) using NONMEM ® 7.2. The model-building strategy for children >3 years has been described in detail before [11]. A pre-planned interim analysis was performed after 30 patients to check the chosen sampling time points and readdress the number of samples and patients.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a “European Pediatric Oncology Off-patents Medicines Consortium” trial

Krischke

Hempel

Völler

et al. 2016

Cancer Chemother Pharmacol

Self Cite

View full text Add to dashboard Cite

PurposeDoxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited.MethodsWe conducted a multinational pharmacokinetic study investigating age dependency of doxorubicin metabolism and elimination in children with cancer. One hundred and one patients treated with doxorubicin according to a cancer-specific national or European therapeutic trial were recruited. Doses of doxorubicin ranged from 10.4 to 57.7 mg/m2. Blood samples for measurement of doxorubicin and its metabolite doxorubicinol were collected after two administrations, with five samples collected in children <3 years and eight in children ≥3 years. A population pharmacokinetic approach was used for analysis, including pharmacogenetic covariates. Natriuretic peptides and cardiac troponins were measured to evaluate their role as early indicators of cardiotoxicity.ResultsAge dependence of doxorubicin clearance was demonstrated, with children less than 3 years having a statistically significant lower clearance (21.1 ± 5.8 l/h/m2) than older children (26.6 ± 6.7 l/h/m2) (p = 0.0004) after correcting for body surface area. No effect of the investigated genetic polymorphisms on the pharmacokinetics could be observed. Although natriuretic peptides were transiently elevated after each doxorubicin administration and troponin levels increased with increasing doxorubicin exposure, only limited correlation could be observed between their blood levels and doxorubicin pharmacokinetics.ConclusionIn the European framework of funding and regulatory support, an add-on study to existing therapeutic trials was developed. The pediatric need concerning missing PK data could be addressed with limited burden for the patients. Empirically used dose adaptations for infants were generally found to be justified based on our PK analyses.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3174-8) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Doxorubicin and doxorubicinol concentrations were measured using a validated HPLC (high-performance liquid chromatography) method (as described in detail before [10]) and were analyzed by population pharmacokinetic methods using nonlinear mixed-effects modeling (NONMEM) [11]. …”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a “European Pediatric Oncology Off-patents Medicines Consortium” trial

Krischke

Hempel

Völler

et al. 2016

Cancer Chemother Pharmacol

Self Cite

View full text Add to dashboard Cite

show abstract

“…The olanzapine model incorporated age, sex and race effects on clearance of the drug. PPK analysis has been utilized to characterize pharmacokinetic profiles of medications such as antibiotic and anticancer agents (Marsot et al, 2012; Kontny et al, 2013). …”

Section: Methodsmentioning

confidence: 99%

Tardive dyskinesia in relation to estimated dopamine D2 receptor occupancy in patients with schizophrenia: Analysis of the CATIE data

Yoshida

Bies

Suzuki

et al. 2014

Schizophrenia Research

View full text Add to dashboard Cite

Objective The objective of this study was to evaluate the relationship between antipsychotic-induced tardive dyskinesia (TD) and estimated dopamine D2 receptor occupancy levels in patients with schizophrenia, using the dataset from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE). Methods The dataset from 218 subjects (risperidone, N=78; olanzapine, N=100; ziprasidone, N=40) who presented with a score of zero on the Abnormal Involuntary Movement Scale (AIMS) at baseline in Phase 1 of the CATIE study, and remained for ≥6 months, was used. Peak and trough dopamine D2 receptor occupancy levels on the day of the AIMS assessment at the endpoint were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our D2 prediction model. The estimated dopamine D2 receptor occupancy levels were compared between patients who presented an AIMS score of ≥2 at endpoint and those with a score of zero, using the Mann-Whitney U test. Results Estimated dopamine D2 receptor occupancy levels at trough were significantly higher in subjects who developed involuntary movements (N=23) than those who did not (N=195) (71.7±14.4% vs. 64.3±19.3%, p<0.05) while no significant difference was found in the estimated peak D2 receptor occupancy between them (75.4±8.7% vs. 72.1±9.9%, p=0.07). When the analyses were separately conducted for the three drugs, there were no significant differences in estimated peak or trough D2 occupancy although the values were consistently numerically higher among those developing involuntary movements. Conclusion Greater dopamine D2 receptor blockade with antipsychotics at trough might increase the risk of tardive involuntary movements although this finding needs to be replicated in larger trials.

show abstract

“…According to the previous studies, the peak concentrations of DOX in plasma by standard infusions in patients are 2-20 µM [39]. In in vitro study, we used 1 µM of DOX in culture model.…”

Section: Discussionmentioning

confidence: 99%

Curcumin Attenuates Doxorubicin-Induced Cardiotoxicity by Inducing Autophagy via the Regulation of JNK Phosphorylation

Katamura¹,

Iwai-Kanai²,

Nakaoka³

et al. 2014

J Clin Exp Cardiolog

View full text Add to dashboard Cite

Background and Objective: Doxorubicin (DOX) has been used in cancer therapy for several decades. However, cardiac complications induced by DOX dose-dependently limit the clinical implication at optimal antitumor efficacy. Curcumin (Cur), a natural compound, has been effective as an anticancer agent in various types of cancers. It also protects against cardiac hypertrophy and heart failure, though its effect on cardiomyopathy caused by DOX treatment is unclear. To elucidate the role of curcumin on heart failure, we used the DOX induced cardiomyopathy model and primary cultured cardiac myocytes. Method and Results:Male C57/BL6 mice were randomized to 4 courses of treatment administered for 4 weeks: Phosphate-Buffered Saline (PBS), Cur, DOX, and DOX+Cur. DOX-treated mice exhibited severe cardiac dysfunction, and the mortality was higher than that in PBS-treated mice. In DOX-treated mice, the number of apoptotic cardiac myocytes was higher and the fibrotic areas were larger than in PBS-treated mice. The cardiotoxic effects of DOX were ameliorated by treatment with Cur. In DOX-treated GFP-LC3 transgenic mice, Cur induced autophagy and decreased apoptosis in the heart. Cur also induced autophagy and suppressed DOX-induced apoptosis in neonatal rat cardiac myocytes. Inhibition of autophagy by 3-methyladenine decreased the cardioprotective effect of Cur. Furthermore, Cur decreased c-Jun N-terminal kinase (JNK) phosphorylation, resulting in reduction of apoptosis. The JNK inhibitor SP600125 abolished these effects. Conclusion:Cur protects the heart from DOX-induced cardiotoxicity by inducing autophagy and decreasing cardiomyocyte apoptosis. The mechanism involves JNK-mediated modification of apoptosis. Induction of cardiac autophagy may be a novel therapeutic approach for preventing DOX-induced cardiotoxicity.

show abstract

Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years

Cited by 38 publications

References 27 publications

Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a “European Pediatric Oncology Off-patents Medicines Consortium” trial

Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a “European Pediatric Oncology Off-patents Medicines Consortium” trial

Tardive dyskinesia in relation to estimated dopamine D2 receptor occupancy in patients with schizophrenia: Analysis of the CATIE data

Curcumin Attenuates Doxorubicin-Induced Cardiotoxicity by Inducing Autophagy via the Regulation of JNK Phosphorylation

Contact Info

Product

Resources

About