Rx Irony: Drug Interactions for Pharmacoenhancement

Drug interactions usually arethought of as being a source ofadverse drug events. Interactionsaffecting the metabolism of theobject drug often result in elevation ofthe object drug's plasma concentrations,leading to toxicity. This mechanism, however,can be employed to boost the plasmaconcentrations of the object drug toachieve or maintain therapeutic concentrationsthat otherwise would be difficultto accomplish.

For example, initially procainamide wasavailable only as an immediate-releaseformulation. Because of its short half-life,procainamide required administrationevery 4 to 6 hours to control arrhythmias.This regimen often led to poor adherenceand loss of rhythm control. It was knownthat cimetidine reduced the renal clearanceof procainamide and could increasethe plasma concentrations of both procainamideand its active metabolite.^1,2Thus, cimetidine occasionally was usedwith procainamide to reduce its eliminationand prolong its half-life. Patients takingcimetidine and procainamide couldreduce the procainamide dosing frequencyto every 8 hours.

Pharmacoenhancement also can beused to lower the cost of therapy byreducing the dose of the object drug.Several authors have suggested thatcyclosporine cost savings could beobtained by coadministration of diltiazem.^3,4 Diltiazem reduces cyclosporineclearance by 40% to 70% and enables asimilar reduction in the dose ofcyclosporine. This reduction leads todirect cost savings on cyclosporine thatare greater than the additional costincurred with the addition of diltiazem.

Most recently, several HIV treatmentregimens have utilized pharmacoenhancementto change the pharmacokineticprofile of one or more proteaseinhibitors.^5,6 Lopinavir is a proteaseinhibitor that, when administered alone,has such low bioavailability that it isunable to produce antiviral concentrationsin the plasma. By combininglopinavir with a low dose of ritonavir, thebioavailability of lopinavir is increasedand the drug is able to achieve antiviralefficacy. The dose of ritonavir is too lowto be of value as an antiviral, but it is adequateto inhibit the intestinal and hepaticCYP3A4 metabolism of lopinavir.Ritonavir also may be inhibiting the P-glycoprotein-mediated efflux of lopinavir.

In addition, ritonavir has been used toboost the effects of other proteaseinhibitors, including saquinavir, indinavir,and amprenavir. Ritonavir increases thearea under the plasma concentrationtime curves, minimum plasma concentration(C^min), and half-life. By increasingthe C^min and half-life, the proteaseinhibitor can be administered at less frequentintervals and still maintain adequateconcentrations to inhibit viral replication.The patient benefits by havingfewer pills to take less frequently.

Pharmacoenhancement can be associatedwith its own risks. The precipitantdrug may have to be administered in adose that not only inhibits the eliminationof the object drug, but also may produceits own side effects. When diltiazem isused as an enhancer of cyclosporine,patients may manifest hypotension,bradycardia, or constipation. The enhancerusually is a potent inhibitor and mayunintentionally inhibit other object drugs,leading to unwanted adverse effects. Ifthe dose of the enhancer is not carefullyadjusted, inadequate or excess increasesin object drug concentrations can occur.

Of course, it is very important for thepatient to adhere to the prescribed drugregimens for both the object drug andthe enhancer drug so that a consistenteffect can be maintained. Because of theneed for a consistent effect, the use ofnatural inhibitors of drug elimination,such as grapefruit juice, is discourageddue to the potential lack of consistencyin inhibition.

The use of drug interactions for thepurpose of pharmacoenhancement isbecoming more common, as more islearned about the desirable characteristicsof both the enhancer and the objectdrugs. The enhancer should produce itseffects on the object drug with a minimumof its own side effects. If increasingthe object drug's concentration is thegoal, the object drug should produceadded therapeutic benefit but with limitedadditional toxicity.

Drs. Horn and Hansten are both professorsof pharmacy at the Universityof Washington School of Pharmacy.For an electronic version of this article,including references if any, visitwww.hanstenandhorn.com.

References

1. Somogyi A, McLean A, Heinzow B. Cimetidine-procainamide pharmacokinetic interaction in man: evidence of competition for tubular secretion of basic drugs. Eur J Clin Pharmacol. 1983;25(3):339-345.

2. Bauer LA, Black D, Gensler A. Procainamide-cimetidine drug interaction in elderly male patients. J Am Geriatr Soc. 1990;38(4):467-469.

3. Bourge RC, Kirklin JK, Naftel DC, Figg WD, White-Williams C, Ketchum C. Diltiazem-cyclosporine interaction in cardiac transplant recipients: impact on cyclosporine dose and medication costs. Am J Med. 1991;90(3):402-404.

4. Smith CL, Hampton EM, Pederson JA, Pennington LR, Bourne DW. Clinical and medicoeconomic impact of the cyclosporine-diltiazem interaction in renal transplant recipients. Pharmacotherapy. 1994;14(4):471-481.

5. Kempf DJ, Marsh KC, Kumar G, et al. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob Agents Chemother. 1977;41:654-660.

6. Motwani B, Khayr W. Pharmacoenhancement of protease inhibitors. Am J Ther. 2006;13:57-63.