Abstract: Brentuximab Vedotin (BV) is an antibody drug conjugate (ADC) approved for the treatment of relapsed classical Hodgkin lymphoma (cHL) and systemic anaplastic T cell lymphoma. BV consists of a CD30 directed antibody cAC10 conjugated by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE). Prior studies analyzing the pharmacokinetics (PK) of BV in normal and impaired renal function patients indicate that the elimination of the ADC and unconjugated cAC10 are through proteolytic degradation into amino acids with the elimination of MMAE occurring through the liver and kidney. However, to date no data evaluating the PK of MMAE in the hemodialysis (HD) population is available. Therefore, we serially obtained serum MMAE levels in a 75 year old female patient diagnosed with relapsed cHL undergoing HD and BV therapy to evaluate the PK and PD behavior of ADC in this population.
Methods: BV was administered at a dose of 1.2 mg/kg every 21 days. Serum samples were obtained within 15 minutes pre and post HD (Mon,Wed, Fri) and pre and post BV. The samples were then analyzed for MMAE drug levels. Concentrations of unconjugated MMAE were measured in plasma, by liquid chromatography and tandem mass spectrometry(LC MS/MS).
Results: The maximum observed plasma MMAE level (Cmax) of 3110 pg/ml and overall decline in plasma concentrations post dosing were similar to phase I studies evaluating the 1.2 mg/kg dose in patients with normal renal function. Areas under the curve (AUC) levels over 21 days also were similar to non HD patients with normal renal function. In addition, pre and post dialysis plasma MMAE levels were similar, indicating that the effect of HD on MMAE levels was negligible.
Conclusion: In a single patient analysis of MMAE levels undergoing HD, levels were consistent with non HD patients suggesting that BV may have similar PK, PD and clinical activity profiles in this population. In addition, HD had minimal effect on MMAE levels indicating little effect of HD on potential efficacy or toxicity. Further studies of BV in patients undergoing HD are warranted to further characterize drug behavior in this population.