Drug Therapy and Down Syndrome

Down syndrome (DS), also known as trisomy 21, is the most common cause of mental retardation.

DS is caused by the presence of an additional 21st chromosome in affected individuals.Patients with DS, especially children, are often on medications to treat various comorbidities that are frequently present.¹ Unfortunately, their unique genetic condition can impact drug therapy in certain circumstances.² Differential drug disposition in patients with DS has been reported with select medications, although the clinical significance is often unclear. There are non-CYP drug metabolizing enzymes and other factors that can impact drug disposition that are located on the 21st chromosome. Altered drug metabolizing enzyme expression combined with physiologic factors unique to the condition can lead to patients with DS exhibiting an altered response to some medications.

This is highlighted when talking about certain cytotoxic chemotherapy agents.Pediatric patients with DS have an elevated risk for certain cancers, such as acute myeloid leukemia and acute lymphoblastic leukemia. Patients with DS and leukemia are often treated with cytotoxic chemotherapy regimens, which generally exhibit excellent efficacy.³

Unfortunately, patients with DS often display increased rates of adverse effects from the chemotherapy. The proposed reasons for elevated adverse drug reactions range from an underlying cellular pro-oxidative state to altered pharmacokinetics of specific agents such as methotrexate or thioguanine.⁴ There are few prospective reports that investigate the impact of chemotherapy in patients with DS; however, the reports that do exist often suggest treating hematological malignancies with reduced doses of select cytotoxic chemotherapeutics combined with close monitoring for toxicity. Pharmacists that are responsible for monitoring or coordinating chemotherapy regimens should be aware that patients with DS may require adjusted dosing to avoid severe toxicities.⁵

Besides cancer, patients with DS also have a higher likelihood of developing Alzheimer’s-like dementia as they age. Treating Alzheimer’s remains difficult in patients with and without DS. Medications like donepezil have been used to treat patients with DS and dementia with some success.⁶ It has also been reported that patients with DS had higher plasma concentration of donepezil compared with patients without DS after receiving the same dose. These patients with the higher plasma concentrations of donepezil also exhibited higher rates of adverse reactions to the drug. Pharmacists should be aware that patients with DS may require non-traditional dosing to achieve better therapeutic efficacy with donepezil.⁷

There are multiple non-clinical reports that suggest altered disposition can occur in DS with many different drugs. Most of these reports are not clinically substantiated; however, they do indicate the potential impact that DS can have on pharmacotherapy. DS is a condition that has a large physiologic effect and may impact drug disposition. Pharmacists should take DS status into account when evaluating medication appropriateness and safety by consulting the most current scientific literature available. This may be especially important when evaluating the safety of cytotoxic chemotherapy regimens.

References

1. Kerins G, Petrovic K, Bruder MB, Gruman C. Medical conditions and medication use in adults with Down syndrome: a descriptive analysis. Down's syndrome, research and practice: the journal of the Sarah Duffen Centre / University of Portsmouth 2008;12(2):141-147.

2. Hefti E, Blanco JG. Pharmacotherapeutic considerations for individuals with Down Syndrome. Pharmacotherapy: J Hum Pharm Drug Therapy. 2016;

doi: 10.1002/phar.1880. [Epub ahead of print]

3. Zwaan CM, Kaspers GJ, Pieters R, et al. Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. Blood. 2002; 99(1):245-251.

4. Hefti E, Blanco JG. Pharmacokinetics of Chemotherapeutic Drugs in Pediatric Patients With Down Syndrome and Leukemia. J Pediatr Hem/Oncol. 2016; 38(4):283-287.

5. Hefti E, Blanco JG. Anthracycline-Related Cardiotoxicity in Patients with Acute Myeloid Leukemia and Down Syndrome: A Literature Review. Cardiovasc Toxicology. 2016;16(1):5-13.

6. Lott IT, Osann K, Doran E, Nelson L. Down syndrome and Alzheimer disease: response to donepezil. Archives Neuro. 2002;59(7):1133-1136.

7. Kondoh T, Nakashima M, Sasaki H, Moriuchi H. Pharmacokinetics of donepezil in Down syndrome. Ann Pharmacotherapy. 2005; 39(3):572-573.