Didanosine, an antiretroviral drug used to treat HIV/AIDS, was developed in the 1980s and approved for medical use in the early 1990s. Its history is marked by its effectiveness as an HIV treatment, particularly as one of the first nucleoside reverse transcriptase inhibitors (NRTIs), but also by concerns over toxicities such as pancreatitis and peripheral neuropathy that necessitated careful monitoring during use. Didanosine was approved in the United States in 1991 and has been included in multiple combination therapies for HIV. Its development featured an emergency use framework and expanded access programs (EAPs) that permitted early use and close monitoring of patients receiving the drug.
BRAND NAMES
Videx – oral formulation
Videx EC – enteric-coated formulation for delayed release.
MECHANISM OF ACTION
It is a synthetic analog of the naturally occurring nucleoside inosine. After entering cells, didanosine is converted to its active form, dideoxyadenosine triphosphate (ddATP), through phosphorylation. This active metabolite competes with the natural substrate, deoxyadenosine triphosphate (dATP), for incorporation into viral DNA by the HIV reverse transcriptase enzyme.
PHARMACOKINETICS
Absorption
Didanosine is rapidly but variably absorbed from the gastrointestinal tract after oral administration. Since it is acid-labile and degraded by gastric acid, it is formulated as buffered tablets or enteric-coated capsules to enhance stability and absorption. Its oral bioavailability is approximately 30–40% in adults.
Distribution
Didanosine has a moderate to high volume of distribution, indicating that it distributes widely into body tissues beyond the plasma. The reported volume of distribution is approximately 0.8–1.0 L/kg in adults.
Metabolism
Didanosine undergoes minimal hepatic metabolism. Unlike many other drugs, it is not significantly metabolized by the cytochrome P450 enzyme system, which reduces the likelihood of drug–drug interactions involving these enzymes.
Elimination
Didanosine is eliminated primarily through the kidneys. About 50–70% of the drug is excreted unchanged in the urine, indicating that renal excretion is the major route of elimination. The drug has a plasma half-life of approximately 1.5 hours, but its intracellular active metabolite has a longer half-life, allowing for sustained antiviral activity.
PHARMACODYNAMICS
Didanosine is a nucleoside reverse transcriptase inhibitor (NRTI) that acts as a prodrug and is converted intracellularly into its active metabolite, dideoxyadenosine triphosphate (ddATP). This active form competes with the natural substrate for incorporation into viral DNA by HIV reverse transcriptase.
ADMINISTRATION
Didanosine is administered orally in the form of buffered tablets or enteric-coated capsules to protect it from degradation by gastric acid. It should be taken on an empty stomach (at least 30 minutes before or 2 hours after meals) because food significantly reduces its absorption.
DOSAGE AND STRENGTH
Didanosine is usually administered orally in the form of enteric-coated capsules or buffered tablets. In adults, the typical dose ranges from 250 mg to 400 mg once daily, depending on body weight, with 250 mg recommended for those under 60 kg and 400 mg for those 60 kg or more. In children, dosing is weight-based, usually 120–200 mg/m²/day divided into two or three doses.
DRUG INTERACTIONS
Didanosine interacts with several drugs that can affect its absorption, efficacy, or toxicity. Antacids and other acid-reducing agents can alter its absorption and should be taken at least 2 hours apart. Co-administration with other antiretrovirals, such as zidovudine or stavudine, increases the risk of peripheral neuropathy, lactic acidosis, or mitochondrial toxicity, while tenofovir can raise didanosine plasma levels, increasing the risk of pancreatitis.
FOOD INTERACTIONS
Didanosine should be taken on an empty stomach because food significantly decreases its absorption, reducing bioavailability and antiviral effectiveness. It is recommended to take the drug at least 30 minutes before or 2 hours after meals.
CONTRAINDICATIONS
Didanosine is contraindicated in patients with a known hypersensitivity to the drug or its components, as well as in those with acute or chronic pancreatitis, severe hepatic impairment, or significant hyperuricemia. Caution is required in individuals with renal impairment, peripheral neuropathy, or a history of lactic acidosis, as these conditions can increase the risk of serious adverse effects.
SIDE EFFECTS
Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain
Neurological: Peripheral neuropathy (numbness, tingling, burning), headache
Metabolic / Hepatic: Lactic acidosis, hepatomegaly with steatosis, elevated liver enzymes, hyperuricemia
Hematologic: Anemia, neutropenia
Ocular / Rare: Retinal changes
Other: Rash, fatigue, insomnia.
OVER DOSAGE
Overdose of didanosine can lead to gastrointestinal symptoms such as nausea, vomiting, and diarrhea, as well as serious complications including lactic acidosis, severe pancreatitis, peripheral neuropathy, and elevated liver enzymes. There is no specific antidote for didanosine overdose, so management is primarily supportive and symptomatic.
TOXICITY
Didanosine toxicity primarily affects the pancreas, liver, and peripheral nerves. The most serious manifestation is pancreatitis, which can be life-threatening. It may also cause lactic acidosis with hepatomegaly and steatosis, especially when used in combination with other nucleoside reverse transcriptase inhibitors. Peripheral neuropathy is another common toxic effect, presenting as numbness, tingling, or burning sensations in the extremities.
