Page 889 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 49 Antiviral Agents 875

include diarrhea (particularly with the buffered formulation), hepa- together. Levels of lamivudine may increase when administered
titis, esophageal ulceration, cardiomyopathy, central nervous system with trimethoprim-sulfamethoxazole. Lamivudine and zalcitabine
toxicity (headache, irritability, insomnia), and hypertriglyceridemia. may inhibit the intracellular phosphorylation of one another;
Concurrent stavudine increases the risk of lactic acidosis. Reports of therefore, their concurrent use should be avoided if possible.
retinal changes and optic neuritis in patients receiving didanosine,
particularly in adults receiving high doses and in children, mandate STAVUDINE
periodic retinal examinations.
Increased levels of didanosine when administered with tenofo-
vir necessitate dose reduction. Concurrent allopurinol or ribavirin The thymidine analog stavudine (d4T) has high oral bioavail-
is contraindicated. The buffer in didanosine tablets interferes with ability (86%) that is not food-dependent. The serum half-life is
the absorption of delavirdine and nelfinavir, necessitating separa- 1.1 hours, the intracellular half-life is 3.0–3.5 hours, and mean
tion in time. The chewable tablets contain phenylalanine, which cerebrospinal fluid concentrations are 55% of those of plasma.
can be harmful to patients with phenylketonuria. Excretion is by active tubular secretion and glomerular filtration.
The major toxicity is a dose-related peripheral sensory neu-
ropathy; incidence may be increased with concomitant neurotoxic
EMTRICITABINE drugs such as didanosine, vincristine, isoniazid, or ribavirin, or
in patients with advanced immunosuppression. Other potential
Emtricitabine (FTC) is a fluorinated analog of lamivudine with adverse effects are pancreatitis, arthralgias, and elevation in serum
a long intracellular half-life (>24 hours), allowing for once-daily aminotransferases. Caution is advised in patients with liver dys-
dosing. Oral bioavailability of the capsules is 93% and is unaf- function. A rare adverse effect is a rapidly progressive ascending
fected by food, but penetration into the cerebrospinal fluid is low. neuromuscular weakness. Lactic acidosis with hepatic steatosis, as
Elimination is by both glomerular filtration and active tubular well as lipodystrophy, appear to occur more frequently in patients
secretion. The serum half-life is about 10 hours. receiving stavudine than in those receiving other NRTI agents.
Emtricitabine is one of the NRTI agents recommended for Stavudine should not be administered with didanosine due to
use in pregnancy (Table 49–5). The combination of tenofovir increased risk of both lactic acidosis and pancreatitis. This com-
and emtricitabine is recommended as pre-exposure prophylaxis to bination has been implicated in several deaths in HIV-infected
reduce HIV acquisition in high-risk persons. pregnant women. Since zidovudine may reduce the intracellular
Both emtricitabine and lamivudine may select for the M184V/I phosphorylation of stavudine, these two drugs should not be used
mutation and therefore should not be used together. together.
The most common adverse effects observed in patients
receiving emtricitabine are headache, diarrhea, nausea, and rash. TENOFOVIR DISOPROXIL FUMARATE
Hyperpigmentation of the palms or soles may be observed (~ 3%),
particularly in African Americans (up to 13%). Clinically signifi- Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide)
cant drug-drug interactions involving emtricitabine have not been analog of adenosine with activity against HIV and HBV. Like
identified. Due to its activity against HBV, exacerbation of HBV the nucleoside analogs, tenofovir competitively inhibits HIV
may occur if therapy is interrupted or discontinued in patients reverse transcriptase and causes chain termination after incorpo-
co-infected with HIV.
ration into DNA. However, only two rather than three intracel-
lular phosphorylations are required for active inhibition of DNA
LAMIVUDINE synthesis.
Tenofovir disoproxil fumarate is a water-soluble prodrug of
Lamivudine (3TC) is a cytosine analog with in vitro activity active tenofovir. The oral bioavailability increases from 25% in
against both HIV-1 and HBV. the fasted state to 39% after a high-fat meal. The prolonged serum
Oral bioavailability exceeds 80% and is not food-dependent. (12–17 hours) and intracellular half-lives allow once-daily dos-
The mean cerebrospinal fluid:plasma ratio of lamivudine is ing. Elimination occurs by both glomerular filtration and active
0.1–0.2. Serum half-life is 2.5 hours, whereas the intracellular tubular secretion, and dosage adjustment in patients with renal
half-life of the triphosphorylated compound is 11–14 hours. insufficiency is recommended.
Lamivudine is predominantly eliminated in the urine by active Tenofovir disoproxil fumarate is one of the NRTI agents rec-
organic cation secretion. ommended for use in pregnancy (Table 49–5). The combination
Lamivudine is one of the recommended NRTI agents for use of tenofovir and emtricitabine is recommended as pre-exposure
in pregnant women (Table 49–5). prophylaxis to reduce HIV acquisition in high-risk persons.
Adverse effects are uncommon but include headache, dizziness, Gastrointestinal complaints (eg, nausea, diarrhea, vomiting,
insomnia, fatigue, dry mouth, and gastrointestinal discomfort. flatulence) are the most common adverse effects but rarely require
Due to its activity against HBV, exacerbation of HBV may occur if discontinuation. Since tenofovir is formulated with lactose, these
therapy is interrupted or discontinued in patients co-infected with may occur more frequently in patients with lactose intolerance.
HIV and HBV. Since both emtricitabine and lamivudine may Cumulative loss of renal function has been observed, possibly
select for the M184V/I mutation, these agents should not be used increased with concurrent use of boosted PI regimens. Acute renal