Ganciclovir and Didanosine: Interaction Details

a) A 68-year old HIV-positive woman receiving both didanosine and valganciclovir experienced significant decline in CD4+ cell counts despite complete viral suppression. She had been prescribed valganciclovir 900 mg twice a day for the treatment of cytomegalovirus enteritis. At the same time she was initiated on HIV therapy (zidovudine/lamivudine 300/150 mg twice a day and lopinavir/ritonavir 400/100 mg twice a day) and Pneumocystis jiroveci pneumonia prophylaxis (trimethoprim/sulfamethoxazole (TMP/SMX) 800/160 mg 3 times a week). Pancytopenia two months later resulted in the discontinuation of TMP/SMX and zidovudine, which were replaced with dapsone and didanosine (200 mg twice a day), respectively. Here CBC normalized, and after one month, the patient's viral load was less than 50 copies/mL and CD4+ cell count was 81 cells/mm3 (20%). Two months later, the CD4+ count increased to 317 cells/mm3 (14%, CD4:CD8 ratio 0.2). However, subsequent cell counts began to decline, and within 9 months had decreased to 83 cells/mm3 (12%) while her viral load remained at less than 50 copies/mL. The patient reported nausea and abdominal discomfort associated with didanosine, so it was replaced with abacavir. After approximately 3 months, the patient's presumed symptoms of didanosine toxicity resolved, CD4+ count increased to 200 cells/mm3 (12%), and within 2 months the CD4+ count was 323 cells/mm3 (15%). The CD4:CD8 ratio also normalized at this time ⁴.

b) Twelve patients received ganciclovir 1000 mg orally every eight hours and didanosine 200 mg two times a day. Steady-state area under the concentration-time curve (AUC) for didanosine increased 111% +/- 114% (range 10% to 493%) when ganciclovir was given with or two hours after didanosine. Ganciclovir AUC was unchanged with concomitant didanosine; it declined slightly (21% +/- 17%) if didanosine was administered two hours earlier. Renal clearance was not significantly altered for either medication ³⁵.

c) Thirty-two AIDS patients who had received concurrent ganciclovir and didanosine were retrospectively studied. Overall, 40.6% of these patients experienced dose-limiting adverse effects attributed to didanosine dosing. Adverse reaction rates were neuropathy 15.6%, diarrhea 9.4%, and pancreatitis 6.3%. Didanosine toxicity was judged not to be higher in patients who had also received ganciclovir compared with those who had not received concurrent ganciclovir. Hematologic toxicity related to ganciclovir did not appear to be higher in patients who used ganciclovir in combination with didanosine compared with patients not receiving didanosine. These investigators concluded that didanosine combined with ganciclovir may be better tolerated than ganciclovir with zidovudine in patients needing antiretroviral therapy along with treatment for cytomegalovirus disease ⁶.

d) When an induction ganciclovir intravenous infusion (5 mg/kg infused over one hour every 12 hours) was administered concurrently with oral didanosine 200 mg every 12 hours, the steady-state didanosine AUC increased 70% +/- 40% and the Cmax increased 49% +/- 48%. In another study, when the standard ganciclovir maintenance intravenous infusion (5 mg/kg infused over one hour every 24 hours) was coadministered with oral didanosine 200 mg every 12 hours, the didanosine AUC increased 50% +/- 26% and the Cmax increased 36% +/- 36% over the first didanosine dosing interval. When ganciclovir was not coadministered with didanosine, the didanosine plasma concentrations were unchanged. The pharmacokinetics of ganciclovir were not altered by the concurrent administration of didanosine. No significant changes in the renal clearance of both drugs were noted during either study ³⁵.

e) Twelve patients who were seropositive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infection completed an open-label, randomized, three-period crossover study investigating the interaction between high-dose oral ganciclovir and didanosine. Each participant received multiple oral doses of didanosine 200 mg every twelve hours, ganciclovir 2000 mg every eight hours, and both drugs concurrently. Didanosine had no significant effects on the pharmacokinetics of ganciclovir. When ganciclovir was administered before didanosine, the mean increases in maximum concentration (Cmax), area under the concentration-time curve (AUC), and percent excreted in the urine were 58.6%, 87.3%, and 100%, respectively. When ganciclovir was given two hours after didanosine, the Cmax, AUC, and percent excreted in the urine were increased by 87.3%, 124%, and 153%, respectively. Because there was no significant change in renal clearance of didanosine, competition for active renal tubular secretion does not appear to be the mechanism of this interaction. Instead, it may be a result of increased didanosine bioavailability which appears to be saturated at an oral ganciclovir dose of 3000 mg daily ⁷.