Didanosine pharmacokinetics

Hepatic function Impairment It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, monitor these patients closely for evidence of didanosine toxicity. 

Loperamide and metoclopramide do not appear to aiter didanosine pharmacokinetics. 

Children-The pharmacokinetics of didanosine administered as Videx EC has not been studied in pediatric patients. 

Saag MS, Sommadossi JP, Rainey D, Myers M, Cort S, Hall D, et al. A pharmacokinetic and antiretroviral activity study of nevirapine in combination with zidovudine plus zalcitabine (ZDV/ddC), zidovudine plus didanosine (ZDV/ddI), or didanosine (ddl) Alone. In The First National Conference on Human Retroviruses and Related Infections, Washington D.C., 1993 102. 

Pharmacokinetics Due to its acid lability, didanosine is administered as either chewable, buffered tablets or in a buffered solution. Absorption is good if taken in the fasting state food causes decreased absorption. The drug penetrates into the CSF but to a lesser extent than AZT. About 55% of the parent drug appears in the urine. 

Pai, S.M. Shukla, U.A. Grasela, T.H. Knupp, C.A. Dolin, R. Valentine, F.T. McLaren, C. Liebman, H.A. Martin, R.R. Pittman, K.A. Barbhaiya, R.H. Population pharmacokinetic analysis of didanosine (2, 3 -dideoxyino-sine) plasma concentration obtained in phase I clinical trials in patients with AIDS or AIDS-related complex. J. Clin. Pharmacol. Ther. 1995, 52, 164—169. 

Morse GD, Fischl MA, Shelton MJ, Cox SR, Driver M, DeRemer M, Freimuth WW. Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother 1997 41(l) 169-74. 

In those who are opioid-dependent, methadone can facilitate adherence to HAART regimens. The pharmacokinetics of the tablet formulations of didanosine and stavudine have been studied in 17 individuals taking stable methadone therapy in comparison with 10 untreated controls (33). Methadone reduced the AUCo 6 by 63% for didanosine and by 25% for stavudine and the C ax by 66% and 44% respectively. These effects appeared to result primarily from reduced systemic availability. Trough concentrations of methadone were comparable to those seen in historical controls, suggesting that the nucleoside analogues did not affect methadone disposition. The authors concluded that larger doses of the tablet formulation (or another type of formulation) may be necessary to provide HAART in subjects taking methadone. 

Japour AJ, Lertora JJ, Meehan PM, Erice A, Connor JD, Griffith BP, Clax PA, Holden-Wiltse J, Hussey S, Walesky M, Cooney E, Pollard R, Timpone J, McLaren C, Johanneson N, Wood K, Booth D, Bassiakos Y, Crumpacker CS. A phase-I study of the safety, pharmacokinetics, and antiviral activity of combination didanosine and ribavirin in patients with HIV-1 disease. AIDS Clinical Trials Group 231 Protocol Team. J Acquir Immune Defic Syndr Hum Retrovirol 1996 13(3) 235-46. 

Tenofovir is not metabolized to a significant extent by CYPs and is not known to inhibit or induce these enzymes. However, tenofovir has been associated with a few potentially important pharmacokinetic drug interactions. A 300-mg dose of tenofovir increased the didanosine AUC by 44 to 60% probably as a consequence of inhibition of the enzyme purine nucleoside phosphorylase by both tenofovir and tenofovir monophosphate. These two drugs probably should not be used together, or if this is essential, the dose of didanosine should be reduced from 400 to 250 mg/day. 

Pharmacokinetics and clinical use Oral bioavailability of ddl is reduced by food and by chelating agents. The drug is eliminated by glomerular filtration and active tubular secretion, and the dose must be reduced in patients with renal dysfunction. Didanosine is used in HAART combination drug regimens. 

Faulds D, Brogden RN. Didanosine. A review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection. Drugs 1992 44 94-116. 

Zhou, X.-J. et al., Population pharmacokinetics of nevirapine, zidovudine, and didanosine in human immunodeficiency virus-infected patients, Antimicrob. Agents Chemother., 43(1) 121-128, 1999. 

A study in 17 subjects taking methadone found that the AUC and maximum levels of didanosine tablets were 57% and 66% lower, respectively, when compared with 10 control subjects. Trough levels of methadone did not differ from historical controls, suggesting that didanosine had no effect on methadone pharmacokinetics. A later study found that there was no reduction in the AUC of didanosine given as enteric-coated capsules. ... 

Gaines K, Wong Jung D, Cimoch P, Lavelle J, Pollard R. Pharmacokinetic interactions with oral ganciclovir zidovudine, didanosine, probenecid. 10th Int Conf AIDS, Yokohama (J )an), 1994. Abstract p7. 

Cidofovir with probenecid modestly decreased levels of trimethoprim and sulfamethoxazole (co-trimoxazole), and caused moderate increases in didanosine levels, but did not alter fluconazole pharmacokinetics. None of these drugs altered cidofovir pharmacokinetics. 

Delavirdine absorption is reduced by the buffered preparation of didanosine. This interaction would not be expected with the enteric-coated preparation of didanosine. Delavirdine does not affect the pharmacokinetics of zidovudine. There is no pharmacokinetic interaction between efavirenz and zidovudine or lamivudine. There is no ciinicaiiy reievant pharmacokinetic interaction between nevirapine and didanosine, iamivudine, stavudine, zaicit-abine or zidovudine. 

MacGregor TR, Lamson MJ, C 1, Pav JW, Saag MS, Elvin AT, Scmmadossi J-P, Myers M, Keims JJ. Steady state pharmacokinetics of nevirapine, didanosine, zalcitabine, and zidovudine combination therapy in HIV-1 positive patients. PharmRes (1995) 12 (9 Si pl), S-101. 

No pharmacokinetic interaction appears to occur between tenofovir and efavirenz or nevirapine. Some ciinicai data have shown a high rate of treatment faiiure when tenofovir is given with enteric-coated didanosine and either efavirenz or nevirapine. 

Rifabutin 300 to 600 mg daily for 12 days did not significantly affect the pharmacokinetics of [buffered] didanosine 167 to 250 mg twice daily in 12 patients with AIDS. The steady-state pharmacokinetics of rifabutin were not affected by didanosine (buffered sachet preparation), which suggests that the buffer used in the didanosine preparation had no effect on rifabutin absorption. However, a case has been reported of a patient taking lopinavir/ritonavir, efavirenz, lamivudine and buffered didanosine who had impaired rifabutin absorption. When rifabutin was taken 30 minutes after didanosine, rifabutin levels were undetectable, but when rifabutin was taken 3 hours after didanosine, rifabutin levels were apparent. ... 

The controlled study suggests that no special precautions are necessary if both drugs are given. However, the case report introduces an element of caution, especially if other drugs that may affect rifabutin pharmacokinetics are used. If indeed rifabutin absorption is affected by antacids (there appear to be no clinical data on this), then giving the drugs at least 2 hours apart, or using the enteric-coated didanosine preparation should avoid the interaction. ... 

Moderate increases in the AUC of zidovudine, not usually requiring dose adjustments, have been seen with atovaquone. However, it may be prudent to regularly monitor for adverse effects. Atovaquone decreased the AUC of didanosine. Neither didanosine nor zidovudine affected atovaquone pharmacokinetics. 

The manufacturer of atovaquone notes that it decreased the AUC of didanosine by 24% in a multiple dose interaction study. There was no change in the pharmacokinetics of atovaquone. ... 

Fluconazole has no significant effect on the pharmacokinetics of didanosine or stavudine, but it may cause an increase in serum zidovudine levels although the clinical importance of this is uncertain. Fluconazole serum levels remain unchanged. 

Itraconazole appears not to affect the pharmacokinetics of zidovudine. Serum levels of itraconazole are markedly reduced when buffered didanosine is given at the same time, but itraconazole and ketoconazole are not affected if buffered didanosine is given 2 hours later. Enteric-coated didanosine has no clinically relevant effect on the pharmacokinetics of flnconazole, itraconazole or ketoconazole. The frequency of haematological toxicity with zidovudine was not increased by ketoconazole. 

Enteric-coated preparation. Enterie-eoated didanosine 400 mg had no significant effect on the pharmacokinetics of fluconazole 200 mg in 14 healthy subjects, and no clinically relevant effect on the pharmacokinetics of itraconazole 200 mg in 25 healthy subjects. Similarly, enteric-coated didanosine 400 mg had no clinically relevant effect on the pharmacokinetics of ketoconazole 200 mg in 24 healthy subjects. Three of the subjects had increased concentrations of ketoconazole with didanosine, but their... 

Hardin TC, Sharkey-Mathis PK, Rinaldi MG, Graybill JR. Evaluation of the pharmacokinetic interaction between itraconazole and didanosine in HIV-infected subjects. Intersci ConfAn-timicrob Agents Chemo er (1995) 35,6. 

Knupp CA, Brater DC, Relue J, Barbhaiya RH. Pharmacokinetics of didanosine and ketoconazole after coadministration to patients seropositive for the human immunodeficiency virus. J Clin Pharmacol (1995) 33, 912-17. 

Trimethoprim, both aione and as co-trimoxazoie (trimethoprim with suifamethoxazoie) reduces the renai ciearance of iamivu-dine, zaicitabine and zidovudine, and therefore raises their pias-ma ieveis. However, the extent of the interaction does not usuaily appear to be ciinicaiiy significant in patients with normal renal function. No clinically significant adverse pharmacokinetic interaction occurs if didanosine is given with co-trimoxazole or trimethoprim. 

SrinivasNR,Kni5)pCA,BatteigerB, Smith R BarbhaiyaRH. A pharmacokinetic interaction study of didanosine coadministered with trimethoprim and/o sulphamethoxazole in HIV seropositive asymptomatic male patients. BrJ CUn Pharmacol (199 41,207-15. 

Interferon alfa does not alter the pharmacokinetics of didanosine or lamivudine to a clinically relevant extent. Interferon alfa and, particularly, interferon beta can cause an increase in the serum levels of zidovudine. HIV-positive patients infected with hepatitis C and treated with interferon alfa and ribavirin may be at special risk of NRTI-associated lactic acidosis. Interleukin-2 appears not to interact significantly with zidovudine. 

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