Update on the Interaction Between Didanosine and Tenofovir Disoproxil Fumarate: Focus on Lactic Acidosis and Pancreatitis
Update on the Interaction Between Didanosine and Tenofovir Disoproxil Fumarate: Focus on Lactic Acidosis and Pancreatitis
Jessica Song, PharmD, Assistant Professor of Pharmacy Practice University of the Pacific, Stockton, CA; Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert
The potential for a clinically detrimental interaction between didanosine and tenofovir disoproxil fumarate (DF) has received considerable attention lately in the medical community.1-7 Tenofovir DF is a nucleotide analog of adenosine 5’-monophosphate, which was approved by the Food and Drug Administration (FDA) for the treatment of human immunodeficiency virus (HIV) infection in October 2001.2 Didanosine, 1 of 7 nucleoside reverse transcriptase inhibitors (NRTIs) marketed in the United States, has been implicated as the causative agent significant adverse events such as lactic acidosis/hepatic steatosis, pancreatitis, and peripheral neuropathy.5,8
Potent, highly active antiretroviral therapy (HAART) regimens containing NRTIs have been shown to lower HIV-associated morbidity and mortality. Consequently, current guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents recommend the combination of at least 3 agents. Therapeutic regimens have included a combination of 3 NRTIs, but the preferred regimen includes either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor in combination with 2 NRTIs.8 Of note, numerous triple-nucleoside regimens containing tenofovir DF have shown high rates of virologic failure in treatment- naïve individuals.9-13 In particular, the combination of tenofovir DF, didanosine, and efavirenz has demonstrated rates of early (at 3 months) virologic failure approaching 50% in previously untreated individuals with high baseline viral loads (> 100,000 copies/mL).12,13
Soon after its introduction to clinical practice, tenofovir DF was recognized to have a marked propensity to produce lactic acidosis and pancreatitis when coadministered with didanosine.1-7 This article will: 1) review the mechanism of lactic acidosis/pancreatitis induction by NRTIs, 2) review the literature reports of lactic acidosis/pancreatitis associated with tenofovir DF and didanosine coadministration, and 3) provide dosing recommendations for didanosine in patients receiving tenofovir DF.
Pathophysiology of NRTI-Induced Lactic Acidosis and Pancreatitis
The pathophysiology of NRTI-induced lactic acidosis and pancreatitis has largely been extrapolated from in vitro studies of the effects of NRTIs on mitochondria.14,15 These studies suggest that NRTI-induced mitochondrial toxicity may be a factor in the development of adverse effects, such as lactic acidosis and pancreatitis. The inhibitory effect of the NRTIs is the greatest on mitochondrial DNA (mtDNA) polymerase, the enzyme responsible for mtDNA replication. Inhibition of mtDNA polymerase causes modification of mitochondrial structure and function, leading to impaired energy production. The consequences of defective mitochondria at the cellular level are decreased oxidative phosphorylation (shifts to anaerobic respiration), intracellular lipid accumulation, and lactic acidosis.14,15
Enzyme assay and cell culture studies have demonstrated the following hierarchy of mitochondrial DNA polymerase inhibition: ≥ zalcitabine ≥ didanosine ≥ stavudine > zidovudine > lamivudine = abacavir = tenofovir.16,17 While the incidence of NRTI-related lactic acidosis is rare, with an estimated frequency of less than 1 per 100 patient-years of therapy15, the mortality rate associated with this syndrome is in the range of 33-60%.1 The risk of lactic acidosis appears to be more common in women, obese patients, those with hepatitis B or C coinfection, and is dependent on nucleoside combination, with cohort studies/retrospective case series indicating the greatest relative risk associated with stavudine + didanosine.15,18,19
At present, the pathogenesis of NRTI-induced pancreatitis has not been elucidated. However, an interesting association between oxygen-derived free radicals and the metabolic pathway of didanosine has been described.20,21 Guo and colleagues observed that didanosine biotransformation results in the formation of various metabolites, including hypoxanthine, xanthine, uric acid, and allantoin. Xanthine oxidase is a major generator of free radicals, suggesting that the heightened activity of this enzyme, secondary to didanosine biotransformation, may be the source of pancreatitis-inducing free radicals.
Didanosine-induced toxicities such as pancreatitis, peripheral neuropathy, and hepatitis appear to be dose-related. Medical literature lends support to the dose-related phenomenon of didanosine-associated toxicity, as shown by the results of a dose-escalating Phase I study of didanosine.22 Thirty-seven patients with AIDS or AIDS-related complex were enrolled in this study and received oral didanosine 0.8-51.2 mg/kg/day for a mean of 21 months. Patients receiving doses of oral didanosine in excess of 9.6 mg/kg/day were at increased risk of experiencing adverse effects, compared with patients receiving lower doses (P-value not reported). A significant interaction exists between didanosine and tenofovir DF, as evidenced by the numerous case reports of lactic acidosis and pancreatitis associated with concurrent administration of these drugs.1-7 Pharmacokinetic studies of tenofovir DF have demonstrated that administering this drug simultaneously, within 2 hours after didanosine, results in a 48%-60% increase in the area under the concentration curve (AUC) of didanosine.23 The exact mechanism of the interaction between tenofovir DF and didanosine has not been elucidated. According to a review of the effect of tenofovir DF on didanosine absorption, there is a possibility that tenofovir DF may increase the AUC of didanosine by either decreasing its renal elimination or enhancing its gastrointestinal absorption.24
Lactic Acidosis Associated With Tenofovir DF/Didanosine
The true incidence of tenofovir DF/didanosine-related lactic acidosis is difficult to estimate, as the FDA’s process for monitoring adverse effects (Adverse Events Reporting Systems) is limited by underreporting, the time frame since the initial marketing of the drug, and the media publicity associated with drug marketing.25 To date, there have been at least 4 published cases of lactic acidosis associated with coadministration of tenofovir DF and didanosine, with the onset of lactic acidosis ranging from several hours to 17 months after initiation of combination therapy.1-4 Of note, confounding factors that may have contributed to the development of lactic acidosis were present in all patients, and included renal insufficiency (n = 2), obesity (n = 1), coinfection with hepatitis C (n = 1), use of higher doses (400 mg/day) of didanosine (n = 3), and the inclusion of stavudine in the antiretroviral treatment regimen (n = 2). Interestingly, one report highlighted the case of a female patient who developed lactic acidosis within hours of starting an antiretroviral regimen that included stavudine, didanosine, and tenofovir DF, despite the fact that the dose of didanosine was lowered to minimize the risk of adverse effects.
Pancreatitis Associated With Reduced-Dose Didanosine/Tenofovir DF
Eight cases of pancreatitis have been attributed to coadministration of tenofovir DF with didanosine, of which 3 reports described pancreatitis during use of didanosine at a reduced dosage (250 mg/day) with tenofovir DF.5,6 In HIV-positive patients who develop pancreatitis following the start of an antiretroviral treatment regimen that includes tenofovir DF and reduced-dosage didanosine (250 mg/day), symptom presentation has been shown to occur within 4-10 weeks. Two cases described patients with low body weights ( 60 kg), and all 3 cases involved concurrent use of stavudine and tenofovir DF/didanosine.5,6 Data from a recent study evaluating the concurrent use of didanosine and tenofovir DF lends support to the findings of published case reports of pancreatitis resulting from combination therapy.7 Martinez and colleagues7 evaluated data from 2 placebo-controlled tenofovir trials which included 393 patients, of which 185 were prescribed the combination of tenofovir DF and either 250 mg or 400 mg didanosine. Five female patients developed pancreatitis, with a median onset time of 22 weeks. In addition, all 5 patients had body weights below 60 kg.
Dosing Recommendations to Minimize Adverse Effects With NRTIs
Because of the known interaction between didanosine and tenofovir DF, the manufacturer of didanosine recommends that its dose should be reduced to 250 mg/day, when coadministered with tenofovir DF to adults weighing at least 60 kg. At present, didanosine dosage recommendations for patients weighing less than 60 kg and receiving concurrent tenofovir DF are not available, but some clinicians have proposed didanosine dosage reduction to 125 mg/day.5 Furthermore, as tenofovir is primarily excreted by the kidneys, patients with creatinine clearances of 30-49 mL/min and 10-29 mL/min should lengthen the dosing interval to every 48 hours and twice weekly, respectively.23 The dose of didanosine should be lowered to 200 mg once daily and 125 mg once daily, respectively, for patients (60 kg) with creatinine clearances of 30-59 mL/min and below 30 mL/min.26
Summary
- Lactic acidosis and pancreatitis have been attributed to coadministration of tenofovir DF with didanosine at a reduced dosage (250 mg/day).
- Reports have shown an onset of lactic acidosis ranging from several hours to 17 months after initiation of combination therapy.
- Pancreatitis has been shown to occur within 4 to 10 weeks after the start of combination therapy.
- Patients weighing less than 60 kg are at heightened risk of developing pancreatitis during combination therapy.
- The dose of didanosine should be reduced to 250 mg/day when it is coadministered with tenofovir DF to adults weighing at least 60 kg (creatinine clearance 60 mL/min).
- Didanosine dosage recommendations for patients weighing less than 60 kg and receiving concurrent tenofovir DF are not available.
References
- Guo Y, et al. Fatal Lactic Acidosis Associated With Coadministration of Didanosine and Tenofovir Disoproxil Fumarate. Pharmacotherapy. 2004; 24:1089-1094.
- Murphy MD, et al. Fatal Lactic Acidosis and Acute Renal Failure After Addition of Tenofovir to an Antiretroviral Regimen Containing Didanosine. Clin Infect Dis. 2003;36:1082-1085.
- Rivas P, et al. Drug Points: Fatal Lactic Acidosis Associated With Tenofovir. BMJ. 2003;327:711.
- Rosso R, et al. Fatal Lactic Acidosis and Mimicking Guillain-Barre Syndrome in an Adolescent With Human Immunodeficiency Virus Infection. Pediatr Infect Dis J. 2003;22:668-670.
- Kirian MA, et al. Acute Onset of Pancreatitis With Concomitant Use of Tenofovir and Didanosine. Ann Pharmacother. 2004;38:1660-1663.
- Callens S, et al. Pancreatitis in an HIV-Infected Person on Tenofovir, Didanosine and Stavudine Containing Highly Active Antiretroviral Treatment. J Infect. 2003;47:188-189.
- Martinez E, et al. Pancreatic Toxic Effects Associated With Co-Administration of Didanosine and Tenofovir in HIV-Infected Adults. Lancet. 2004;364:65-67.
- Guidelines For the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 29, 2004. Available at: http://aidsinfo.nih.gov/guidelines/. Accessed February 21, 2005.
- Farthing C, et al. Early Virologic Failure in a Pilot Study Evaluating the Efficacy of Abacavir, Lamivudine, and Tenofovir in the Treatment-Naïve HIV-Infected Patients. The 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment. Paris. July 13-16, 2003. Abstract 43.
- Ladman R, et al. Low Genetic Barrier to Resistance is a Possible Cause of Early Virologic Failures in Once-Daily Regimen of Abacavir, Lamivudine, and Tenofovir: The Tonus Study. 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, February 8-11, 2004. Abstract 52.
- Jemsek J, et al. Poor Virologic Responses and Early Emergence of Resistance in Treatment-Naïve, HIV-Infected Patients Receiving a Once-Daily Triple Nucleoside Regimen of Didanosine, Lamivudine, and Tenofovir DF. 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, February 8-11, 2004. Abstract 51.
- Podzamczer D, et al. Early Virological Failure and Occurrence of Resistance in Naïve Patients Receiving Tenofovir, Didanosine, and Efavirenz. Antivir Ther. 2004;9:S172.
- Moyle G, et al. Early Virological Failure in Persons With Viral Loads > 100,000 cps/mL and CD4 Counts < 200 cells/mm3 Receiving DDL/Tenofovir/Efavirenz as Initial Therapy: Results From a Randomized Comparative Trial. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004; Washington DC. Abstract H-566.
- Cossarizza A, et al. Antiretroviral Nucleoside and Nucleotide Analogues and Mitochondria. AIDS. 2004;18:137-151.
- Moyle G. Toxicity of Antiretroviral Nucleoside and Nucleotide Analogues: is Mitochondrial Toxicity the Only Mechanism? Drug Saf. 2000;23:467-481.
- Birkus G, et al. Assessment of Mitochondrial Toxicity in Human Cells Treated With Tenofovir: Comparison With Other Nucleoside Reverse Transcriptase Inhibitors. Antimicrob Agents Chemother. 2002; 46:716-723.
- Martin JL, et al. Effects of Antiviral Nucleoside Analogs on Human DNA Polymerases and Mitochondrial DNA Synthesis. Antimicrob Agents Chemother. 1994;38:2743-2749.
- Boubaker K, et al. Hyperlactatemia and Antiretroviral Therapy: The Swiss HIV Cohort Study. Clin Infect Dis. 2001;33:1931-1937.
- Coghlan ME, et al. Symptomatic Lactic Acidosis in Hospitalized Antiretroviral-Treated Patients With Human Immunodeficiency Virus Infection: A Report of 12 Cases. Clin Infect Dis. 2001;33:1914-1921.
- Tay LK, et al. Metabolism of 14C-2’, 3’-Dideoxyinosine By the In Situ Perfused Rat Liver Preparation. Biopharm Drug Dispos. 1991;12:285-297.
- Folch E, et al. Free Radicals Generated By Xanthine Oxidase Mediate Pancreatitis-Associated Organ Failure. Dig Dis Sci. 1998;43:2405-2410.
- Yarchoan R, et al. Long-Term Toxicity/Activity Profile of 2’,3’ Dideoxyinosine in AIDS or AIDS-Related Complex. Lancet. 1990;336:526-529.
- Gilead Sciences, Inc. Viread (Tenofovir Disoproxil Fumarate) Package Insert. Foster City, CA; 2004.
- Fulco PP, et al. Effect of Tenofovir on Didanosine Absorption in Patients With HIV. Ann Pharmacother. 2003;37:1325-1328.
- Owens RC, et al. Torsades De Pointes Associated With Fluoroquinolones. Pharmacotherapy. 2002; 22:663-672.
- Bristol-Myers Squibb Company. Videx EC (Didanosine) Package Insert. Princeton, NJ; 2004.
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