(W-054) Effects of sparse sampling in the characterization of leuprolide pharmacokinetics and pharmacodynamics in patients with prostate cancer

Silvia Illamola, PharmD, PhD – Research Associate, Department of Experimental and Clinical Pharmacology (ECP), University of Minnesota; Benjamin Maughan, MD – Assistant Professor, Huntsman Cancer Institute, University of Utah; Angela Birnbaum, PhD, FAES – Professor, Department of Experimental and Clinical Pharmacology (ECP), University of Minnesota; Neeraj Agarwal, MD, FASCO – Professor, Huntsman Cancer Institute, University of Utah; Joseph Rower, PhD – Assistant Professor, University of Utah; Jadon Wagstaff, MS – Biostatistician II, Huntsman Cancer Institute, University of Utah; Julia Batten, APRN – Nurse Practitioner, Huntsman Cancer Institute, University of Utah; Robert Ward, MD – Emeritus, Professor, University of Utah; Catherine Sherwin, PhD – Prof, Wright State University, Boonshoft School of Medicine

Long acting injectable (LAI) medications utilize polymeric microspheres to control the release of the drug after intramuscular injection. Leuprolide is a LAI which is formulated to be released over a few days to several months. Analyzing data with complicated pharmacokinetic characteristics such as absorption as seen with LAIs can be challenging, and rich sampling is usually required. We aimed to evaluate the feasibility of characterizing the pharmacokinetics (PK) of leuprolide formulations in patients with prostate cancer using a sparse sampling study design that mirrors clinical practice.

This study is an observational study in a group of 47 patients (46 to 83 years) diagnosed with advanced prostate cancer treated with 22.5 mg of leuprolide every three months. Blood samples were collected during clinic visits (pre-dose, ~2h, ~2weeks, and ~4 weeks post-dose). Samples were used to measure 1) leuprolide plasma concentrations for pharmacokinetic analysis, and 2) luteinizing hormone and testosterone plasma concentrations to monitor pharmacodynamic effects. As the sparse sampling design did not allow estimation of leuprolide PK parameters, we performed a simulation study using a previously published PK model of leuprolide in subjects with prostate cancer (n=100 simulations in 25 individuals using intramuscular administration with intensive sampling, and n=100 simulations in 25 individuals with intravenous design) [1] to characterize the extent of variability in leuprolide concentrations and to evaluate the sparse sampling design typical in clinical practice.

There was a high variability in measured leuprolide concentrations across patients who were receiving the same dose. Leuprolide concentrations drawn at ~2 hours post-dose and after 10 days had a median of 2.99 ng/mL (range: 0.17 - 23.50 ng/mL) and of 0.22 ng/mL (range: 0.03 – 1.04 ng/mL), respectively. Simulated leuprolide concentrations corresponded with measured concentrations. Few concentrations (4.5%) were below the lower limit of quantification (0.04 ng/mL). Most of the measurements below the lower limit of quantification (83.1%) occurred after 10 days. Luteinizing hormone and testosterone plasma concentrations were suppressed within the first 2 weeks and mirrored outcome data found in clinical practice when treating prostate patients with LAI formulations.

This study demonstrates that measuring of drug concentrations at early time points is required to allow sufficient characterization of absorption PK parameters for slow-release injectable medications. As LAI formulations are becoming more accessible, studies need to be designed that incorporate sufficient capturing of PK and pharmacodynamic measures to ensure that the duration of effect is thoroughly assessed and to determine when a subsequent dose is needed.

Citations: [1] Lim CN, Salem AH. A semi-mechanistic integrated pharmacokinetic/pharmacodynamic model of the testosterone effects of the gonadotropin-releasing hormone agonist leuprolide in prostate cancer patients. Clin Pharmacokinet. Sep 2015;54(9):963-73. doi:10.1007/s40262-015-0251-9