Limits...
A model of hypertension and proteinuria in cancer patients treated with the anti-angiogenic drug E7080.

Keizer RJ, Gupta A, Mac Gillavry MR, Jansen M, Wanders J, Beijnen JH, Schellens JH, Karlsson MO, Huitema AD - J Pharmacokinet Pharmacodyn (2010)

Bottom Line: Modeling was performed in NONMEM, and direct and indirect response PK-PD models were evaluated.A previously developed PK model was used.This model may guide clinical interventions and provide treatment recommendations for E7080, and may serve as a template model for other drugs in this class.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Slotervaart Hospital, Amsterdam, The Netherlands. ron.keizer@slz.nl

ABSTRACT
Hypertension and proteinuria are commonly observed side-effects for anti-angiogenic drugs targeting the VEGF pathway. In most cases, hypertension can be controlled by prescription of anti-hypertensive (AH) therapy, while proteinuria often requires dose reductions or dose delays. We aimed to construct a pharmacokinetic-pharmacodynamic (PK-PD) model for hypertension and proteinuria following treatment with the experimental VEGF-inhibitor E7080, which would allow optimization of treatment, by assessing the influence of anti-hypertensive medication and dose reduction or dose delays in treating and avoiding toxicity. Data was collected from a phase I study of E7080 (n = 67), an inhibitor of multiple tyrosine kinases, among which VEGF. Blood pressure and urinalysis data were recorded weekly. Modeling was performed in NONMEM, and direct and indirect response PK-PD models were evaluated. A previously developed PK model was used. An indirect response PK-PD model described the increase in BP best, while the probability of developing proteinuria toxicity in response to exposure to E7080, was best described by a Markov transition model. This model may guide clinical interventions and provide treatment recommendations for E7080, and may serve as a template model for other drugs in this class.

Show MeSH

Related in: MedlinePlus

Visual predictive checks of systolic (a) and diastolic (b) BP, for patient treated at the MTD of 25 mg E7080 qd. Solid line and dark grey area represents median observed and predicted 95% CIs. Dashed lines and light grey areas represent the 10 and 90% percentiles of the observed values, and the 95% CI of the model predicted percentiles
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2921067&req=5

Fig2: Visual predictive checks of systolic (a) and diastolic (b) BP, for patient treated at the MTD of 25 mg E7080 qd. Solid line and dark grey area represents median observed and predicted 95% CIs. Dashed lines and light grey areas represent the 10 and 90% percentiles of the observed values, and the 95% CI of the model predicted percentiles

Mentions: Overall, although the dataset was obtained from a single phase I study, the dose range that was studied provided enough data to capture an exposure–response relationship, both for BP and for the probability of experiencing proteinuria. The predictive checks that were generated (Figs. 2, 3, 4) showed that the model was describing the observed clinical data with satisfactory precision, which is especially important if the model is to be used for simulation purposes, e.g. the evaluation of dosing strategies. Such simulations have been planned, and include e.g. the evaluation of a hypertension intervention scheme, and the evaluation of an adaptive treatment design, using BP to guide intra-patient dose escalation.Fig. 2


A model of hypertension and proteinuria in cancer patients treated with the anti-angiogenic drug E7080.

Keizer RJ, Gupta A, Mac Gillavry MR, Jansen M, Wanders J, Beijnen JH, Schellens JH, Karlsson MO, Huitema AD - J Pharmacokinet Pharmacodyn (2010)

Visual predictive checks of systolic (a) and diastolic (b) BP, for patient treated at the MTD of 25 mg E7080 qd. Solid line and dark grey area represents median observed and predicted 95% CIs. Dashed lines and light grey areas represent the 10 and 90% percentiles of the observed values, and the 95% CI of the model predicted percentiles
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2921067&req=5

Fig2: Visual predictive checks of systolic (a) and diastolic (b) BP, for patient treated at the MTD of 25 mg E7080 qd. Solid line and dark grey area represents median observed and predicted 95% CIs. Dashed lines and light grey areas represent the 10 and 90% percentiles of the observed values, and the 95% CI of the model predicted percentiles
Mentions: Overall, although the dataset was obtained from a single phase I study, the dose range that was studied provided enough data to capture an exposure–response relationship, both for BP and for the probability of experiencing proteinuria. The predictive checks that were generated (Figs. 2, 3, 4) showed that the model was describing the observed clinical data with satisfactory precision, which is especially important if the model is to be used for simulation purposes, e.g. the evaluation of dosing strategies. Such simulations have been planned, and include e.g. the evaluation of a hypertension intervention scheme, and the evaluation of an adaptive treatment design, using BP to guide intra-patient dose escalation.Fig. 2

Bottom Line: Modeling was performed in NONMEM, and direct and indirect response PK-PD models were evaluated.A previously developed PK model was used.This model may guide clinical interventions and provide treatment recommendations for E7080, and may serve as a template model for other drugs in this class.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Slotervaart Hospital, Amsterdam, The Netherlands. ron.keizer@slz.nl

ABSTRACT
Hypertension and proteinuria are commonly observed side-effects for anti-angiogenic drugs targeting the VEGF pathway. In most cases, hypertension can be controlled by prescription of anti-hypertensive (AH) therapy, while proteinuria often requires dose reductions or dose delays. We aimed to construct a pharmacokinetic-pharmacodynamic (PK-PD) model for hypertension and proteinuria following treatment with the experimental VEGF-inhibitor E7080, which would allow optimization of treatment, by assessing the influence of anti-hypertensive medication and dose reduction or dose delays in treating and avoiding toxicity. Data was collected from a phase I study of E7080 (n = 67), an inhibitor of multiple tyrosine kinases, among which VEGF. Blood pressure and urinalysis data were recorded weekly. Modeling was performed in NONMEM, and direct and indirect response PK-PD models were evaluated. A previously developed PK model was used. An indirect response PK-PD model described the increase in BP best, while the probability of developing proteinuria toxicity in response to exposure to E7080, was best described by a Markov transition model. This model may guide clinical interventions and provide treatment recommendations for E7080, and may serve as a template model for other drugs in this class.

Show MeSH
Related in: MedlinePlus