DRUG INTERACTION CASE STUDIES CASE STUDY 1 A

DRUG INTERACTION: CASE STUDIES

CASE STUDY 1 • A 39 -year-old man was admitted to the hospital with new onset seizures and a 2 -week history of blurred vision. • After a work-up, diagnoses included advanced HIV infection, CMV retinitis, and probable toxoplasmic encephalitis. • Sulfadiazine and pyrimethamine were started for treatment of toxoplasmic encephalitis. • Phenytoin was initiated at a dosage of 300 mg daily for seizure. • The patient also received valganciclovir for treatment of CMV retinitis. • After experiencing another seizure while hospitalized, the phenytoin dose was increased to 300 mg twice daily on 19 September. • Antiretroviral therapy with efavirenz (EFV), emtricitabine, and tenofovir was started on 22 September. • A plan was made to monitor both phenytoin and EFV plasma concentrations to ensure adequate safety and therapeutic efficacy.

• On 30 September, the first measurement of EFV plasma concentration was obtained, with a result of 0. 34 µg/m. L. • Target EFV concentrations of 1 – 4 µg/m. L or >2. 2 µg/m. L have been proposed in the literature, while concentrations <1. 1 µg/m. L have been associated with treatment failure. • Because EFV has a long half-life (40 -55 hours), it was recognized the plasma level could be low because the sample was obtained prior to steady-state.

• 1. Other than obtaining the level before achieving steady-state, what are other potential explanations for the low EFV exposure? Consider the patient’s concurrent medications.

• There was concern that phenytoin was the cause of the lower-thanexpected EFV concentrations. • As persistently low EFV exposure could put the patient at risk for treatment failure and development of virologic resistance, it was decided to rapidly taper the phenytoin and commence therapy with levetiracetam —an anticonvulsant without CYP modulation potential. • In the meantime, the EFV dosage was increased from 600 to 800 mg/day under the assumption that CYP induction could continue for up to 7 -14 days after discontinuation of phenytoin. • Prior to implementation of the EFV dosage increase, a 2 nd test result returned an EFV concentration of 0. 58 µg/m. L.

• The patient received his last dose of phenytoin on 22 October. • A third measurement of EFV level was obtained on 9 November, after what was predicted to be sufficient time for reversal of phenytoin’s enzyme induction. • The result was an EFV concentration of 2. 5 µg/m. L. At that time the EFV dosage was reduced back to the recommended dose of 600 mg/day. • On 16 November, the patient had an HIV RNA of 189 copies/m. L and a CD 4 cell count of 100 cells/mm 3, which indicated continued virologic response to antiretroviral therapy. • The patient’s latest measured EFV, after 3 weeks at a dosage of 600 mg/day, was 2 µg/m. L. • Phenytoin levels measured after EFV therapy initiation showed a gradual increase, despite a stable phenytoin dosage and no changes in

EXPLANATION • Phenytoin is a known CYP 3 A 4 inducer. • It acts by increasing DNA transcription, which results in the synthesis of new CYP 3 A 4. • EFV is extensively metabolized by CYP 3 A 4 and CYP 2 B 6. • Therefore, phenytoin may increase in EFV metabolism and causes a decrease in EFV plasma concentration.

2. Explain the likely reasons for the increase in phenytoin plasma levels • The increase in phenytoin plasma concentrations in this case was possibly the result of inhibition of CYP 2 C 9 and CYP 2 C 19 by EFV. • In vitro studies have shown that EFV inhibits CYP 2 C 9 and CYP 2 C 19 enzymes, with Ki values in the range of observed EFV plasma concentrations (2. 7– 5. 4 mg/m. L). • Interpretation of this interaction may be complicated by the concurrent use of sulfadiazine, which has been shown to decrease phenytoin clearance by 45%.

Case study adapted from: • Robertson SM, Penzak SR, Lane J, Pau AK, Mican JM. A potentially significant interaction between efavirenz and phenytoin: a case report and review of the literature. Clin Infect Dis. 2005; 41: e 15 -18.

CASE STUDY 2 • A 78 -year-old man visited a hospital for cough and increased sputum, for which he was prescribed clarithromycin, a macrolide antibiotic. • The following day he was admitted to another hospital for loss of consciousness. • His medical history included hypertension, atrial fibrillation and chronic kidney disease. • He reportedly took two calcium-channel blockers, nifedipine and diltiazem, as well as carvedilol (a beta-blocker), irbesartan (angiotensin receptor blocker), isosorbide dinitrate, and dypiridamole. • At admission his blood pressure was 96/38 mm Hg, relative to a historical baseline value of 140/70 mm Hg. • His pulse rate was 44 bpm. • Physical examination showed no abnormal findings and his peripheries were warm.

• The differential diagnoses considered were septic shock, cardiogenic shock and hypovolaemic shock. • However, the patient’s respiratory symptoms were mild, and he required no supplemental oxygen. • Cardiogenic shock was ruled out by transthoracic echocardiogram. • Even after his heart rate increased to 70 bpm after atropine administration, his blood pressure showed no improvement. • He showed no signs of fluid loss to suggest hypovolemic shock. • After other causes were ruled out, the hypotension was attributed to a drug interaction between a calcium-channel blocker and clarithromycin.

1. Discuss the complex drug interactions that contributed to hypotension in this patient.

EXPLANATION • Calcium-channel blockers, including nifedipine and diltiazem, are metabolized extensively by CYP 3 A 4. • Clarithromycin is a strong inhibitor of CYP 3 A 4, and diltiazem and its metabolites are also CYP 3 A 4 inhibitors. • Inhibition of CYP 3 A 4 metabolism can cause excessive exposure of calcium-channel blockers, which can result in vasodilatory hypotension. • In addition, the combination of two calcium-channel blockers and a betablocker can lower cardiac output due to bradycardia and thus worsen hypotension.

• In this case, the hypotension presented one day after the patient began using a combination of calcium-channel blockers and clarithromycin. • Typically inhibition of CYP 3 A by clarithromycin and erythromycin does not occur immediately, as these agents are mechanism-based inhibitors. • In this case, however, the patient was taking two calcium-channel blockers and carvedilol, which may have contributed to the onset of symptoms.

• Benzothiazepine calcium-channel blockers have negative inotropic and chronotropic effects and, in excess, can disturb the cardiac conduction system. • β-Blockers prevent the compensating increase in heart rate. Consequently, these medications would effectively worsen hypotension. • Since carvedilol is also metabolized by CYP 3 A 4, its plasma concentrations may also have been increased by clarithromycin. • Finally, the patient’s age might be expected to contribute to the severity of the adverse outcome that resulted from this complex drug interaction.

Case study adapted from: • Takeuchi S, Kotani Y, Tsujimoto T. Hypotension induced by the concomitant use of a calcium-channel blocker and clarithromycin. BMJ Case Rep. Jan 9, 2017

• Task: – Case study of Ibuprofen interaction – Reference from www. saurabhmaru. wordpress. com