Nonlinear correlation between axitinib dose, dBP increase

Nov 18 2014

By Shreeya Nanda, Senior medwireNews Reporter

A pharmacokinetic–pharmacodynamic model shows that diastolic blood pressure (dBP) rises with increasing doses of axitinib in patients with metastatic renal cell carcinoma (mRCC), US researchers report, although this relationship is not linear.

Ying Chen, from Pfizer Inc, San Diego, California, and co-workers developed the model based on ambulatory dBP measurements and pharmacokinetic data collected from 62 patients with previously untreated mRCC who were given the tyrosine kinase inhibitor.

Specifically, patients received axitinib 5 mg twice daily for 4 weeks, after which eligible participants (blood pressure ≤150/90 mmHg, no grade 3 or 4 axitinib-related toxicities, no dose reduction and use of two or fewer concurrent antihypertensive medications for 2 consecutive weeks during the lead-in period) were randomly assigned to receive axitinib- or placebo-titration.

At this point, the twice daily dose was titrated stepwise to 7 mg (5 mg axitinib and 2 mg of axitinib or placebo) and then, 2 weeks later, to 10 mg (5 mg axitinib and 5 mg of axitinib or placebo). Serial and sparse pharmacokinetic data were collected at specified time points.

The researchers selected the indirect-response, maximum-effect (E_max) model to determine the exposure-driven impact of axitinib on dBP.

E_max was estimated as 20.8% and the concentration at which 50% of the maximal increase in dBP was achieved was 12.4 ng/mL. There was good correlation between the ambulatory dBP observed over a 24-hour period and that predicted by the model on a population and individual level.

Simulations using the E_max model for an axitinib dose of between 2 mg and 20 mg twice daily predicted an increase in dBP of 5.1 to 11.5 mmHg higher than that recorded at baseline on day 4 of axitinib treatment. However, only a minimal additional increase for these doses was predicted on day 15, at 5.7 to 12.0 mmHg higher than baseline.

“Once steady state was achieved, no additional changes in dBP over time were expected based on the model”, the researchers write in Clinical Pharmacokinetics.

Chen et al say that although their data suggest that increases in axitinib concentration are associated with increases in dBP, the relationship is not proportional, and add that “this model captures the circadian rhythm in the [baseline] 24-h BP profile, thereby separating the drug effect from the diurnal changes.”

They continue: “This suggests that dose adjustments to decrease axitinib exposure may be useful in managing drug-associated increases in dBP; however, increased dBP during axitinib treatment is not a proxy for drug exposure and, therefore, dBP measurements should not be used exclusively to guide axitinib dosing.”

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