Model-based Precision Dosing Can Limit Melphalan Toxicity in Patients Undergoing Stem Cell Transplantation
Published May 2018 | Clinical Pharmacokinetics
In children undergoing high-dose chemotherapy in preparation for hematopoietic stem cell transplantation, melphalan is something of a necessary evil.
A bi-functional alkylating agent derived from mustard gas, it is aggressive at halting—or at least slowing—the growth of cancer cells. It is one of the most widely used drugs in conditioning regimens for patients with malignant diseases.
But the current dosing strategy is still based on body surface area, an imprecise gauge adapted from adult dosing. It has resulted in unnecessarily high rates of oral mucositis and toxicity of the liver and gastrointestinal tract.
Now, a team of researchers led by author Kana Mizuno, PhD, and Alexander Vinks, PharmD, PhD, Director, Division of Clinical Pharmacology, has developed a pharmacokinetic model and optimal sampling strategy. The feasibility was tested in five children whose median age was 5.6 years.
The key: capture each child’s pharmacokinetic fingerprint as a dosage guide. The final model includes body weight and creatinine clearance as predictors of toxicity risk.
“There is a paradox in the way we develop drugs, namely for average kids. Well, there is no such thing,” says Vinks, who also serves as Scientific Director of Pharmacy Research. “In melphalan, if you give children the same dose, they all will have differing amounts of it in their bodies. There is tremendous variability. This is precision dosing.”
Unlike therapies involved in chronic treatment, he points out, clinicians only get one chance to achieve optimal dose. Study authors also included colleagues in the Division of Bone Marrow Transplantation and Immune Deficiency, and the University of Cincinnati Cancer Institute.
Asked if the findings provided any surprises, Vinks paused. “There’s always unexpected things,” he says. “It predicts better than I expected.”
