Oxandrolone Coadministration Does Not Alter Plasma Propranolol Concentrations in Severely Burned Pediatric Patients

Abstract

The systemic impact of severe burn injury results in a variety of disorders that require therapeutic intervention. Propranolol, a nonselective β1, β2-adrenergic receptor antagonist, reduces resting heart rate and cardiac work caused by elevated circulating catecholamines. Oxandrolone, a testosterone mimetic, promotes protein synthesis and anabolism to counter muscle wasting. Coadministration of these drugs is expected to synergistically improve patient outcomes. Testosterone administration is known to alter β-adrenergic receptor-mediated signaling. Here, we determined whether the coadministration of oxandrolone alters plasma propranolol concentrations. Ninety-two pediatric patients with burns covering ≥30% of the TBSA were enrolled in this institutional review board-approved study and randomized to receive propranolol (n = 49) or oxandrolone + propranolol (n = 43). Plasma propranolol concentrations were determined following two dosing strategies: Q6 (liquid formulation; n = 86) and Q24 (extended-release capsule; n = 22). Samples were drawn before drug administration and at regular intervals throughout the next two dosing periods. Heart rate and blood pressure were recorded throughout the study. Propranolol half-life was 3.3 hours for the Q6 drug dosing frequency (P < .0001) and 11.2 hours for the Q24 strategy (P < .0001). Percentage of predicted heart rate declined by 2.8% for each doubling of the propranolol concentration in the Q6 dosing schedule (P < .0001). Percentage of predicted heart rate declined by 2.5% for each doubling of propranolol concentration on the Q24 dosing schedule (P < .0001). Maximum and minimum propranolol plasma concentrations were similar with either dosing regimen. The addition of oxandrolone did not affect any of the measured parameters. Oxandrolone coadministration does not alter propranolol's plasma concentration, half-life, or effect on heart rate. This study is registered at clincialtrials.gov: NCT00675714.

Figure 1.

Consort diagram. Of 530 patients admitted to our institution between January 2012 and June 2015, 108 patients were included in our study. OXPROP, oxandrolone plus propranolol; PROP, propranolol; SHC, Shriners Hospitals for Children.

Figure 2.

Oxandrolone coadministration does not change plasma propranolol kinetic profiles. Plasma PPL concentrations for both S- and R-enantiomers with and without oxandrolone coadministration are shown for both Q6 (A, B) and Q24 (C, D) dosing strategies. OXPROP, oxandrolone plus propranolol; PPL, propranolol; PROP, propranolol.

Figure 3.

Oxandrolone coadministration does not change maximum or minimum plasma propranolol concentrations. Maximum (A) and minimum (B) concentrations for both propranolol enantiomers with or without oxandrolone coadministration are shown for both Q6 and Q24 dosing strategies. Cmax, maximum concentration; Cmin, minimum concentration; OXPROP, oxandrolone plus propranolol; PPL, propranolol.

Figure 4.

Oxandrolone coadministration does not alter percent of predicted heart rate. Percent predicted heart rate with or without oxandrolone coadministration during the study period for the Q6 and Q24 dosing strategies. %Pred HR, percent of predicted heart rate; OXPROP, oxandrolone plus propranolol; PPL, propranolol.

Figure 5.

Oxandrolone coadministration does not alter blood pressure. Systolic (A) and diastolic (B) blood pressure with or without oxandrolone coadministration during the study period for the Q6 and Q24 dosing strategies. DBP, diastolic blood pressure; OXPROP, oxandrolone plus propranolol; PROP, propranolol; SBP, systolic blood pressure.