Purpose: Great variability exists in the tolerability of chemotherapy among cancer patients. Many chemotherapeutic agents have been associated with dose limiting toxicities and adverse events resulting in dose reductions. Classically, these agents have been dosed by adjusting for body surface area (BSA), however, several studies have shown a poor relationship between BSA, predicted drug exposure and pharmacokinetic (PK) parameters. We hypothesize differences in body composition may underlie some of the heterogeneity in chemotherapy toxicities. Additionally, low lean mass in adult cancer patients is highly prevalent and has been associated with an increased risk for chemotherapeutic toxicity and shorter survival. In this trial, we compared estimated lean mass by well-established equations and compared these to CT-derived measured values. To support the development of a population structural model, estimated and measured values were compared to outcome data and pharmacokinetic parameters.
Methods: AR-42 was dosed as a single-agent in an open-label phase I dose escalation (3+3) study in adult patients with advance or recurrent solid tumors. Patients received AR-42 (30, 60 or 80mg) 3x/week in cycles of 28 days followed by a 7 day off treatment period. Venous blood samples were collected on cycle 1 day 1 and cycle 1 day 19. Pharmacokinetic parameters were generated from plasma data by WinNonlin (V 6.0, Pharsight, Mountain View, CA). CT scans at L3 from cycle 1 were analyzed using Slice‐O‐Matic software (v.4.3 Tomovision, Montreal Canada). The total cross‐sectional area of skeletal muscle was quantified from images using pre‐established thresholds (−29 to +150 HU) for muscle tissue. Total cross‐sectional skeletal muscle area (cm2) was normalized to squared height (m2) and expressed as a skeletal muscle index (SMI) (cm2/m2). Sarcopenia was determined using SMI cutoffs (<32.4 cm2/m2 for females and <55.4 cm2/m2 for males). Fitting of plasma data was performed using a two compartment first order absorption model by NONMEM, v. 7.1.2 (Icon, Hanover, MD, USA).
Results: We observed estimated patient lean mass was consistently higher than CT-derived values. Furthermore, relationships between patient plasma PK parameters and estimated as well as measured lean mass values were explored. There was a trend for decreased volume of distribution (Vd) and clearance (CL) in patients who were classified as sarcopenic using skeletal muscle index (SMI) cutoffs (<32.4 cm2/m2 for females and <55.4 cm2/m2 for males).
Conclusion: Measured lean body mass is lower than estimated lean mass in advanced cancer patients. AR-42 volume of distribution is higher in non-sarcopenic patients but no apparent differences exist in obese vs. normal weight patients with solid tumors. Population modeling will be used to evaluate SMI, BMI and weight as co-variates for AR-42 plasma pharmacokinetics.
Amir Mortazavi– Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University
Kristin Dittmar– Division of Interventional Radiology, Department of Radiology, College of Medicine, The Ohio State University
Alison Walker– Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University
Craig Hofmeister– Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University
Mitch Phelps– Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University
Chris Coss– Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University