Page 900 - Basic _ Clinical Pharmacology ( PDFDrive )

886 SECTION VIII Chemotherapeutic Drugs

Combination therapies may reduce the development of resistance. the negative strand, and synthesis of the positive strand of HBV
The optimal duration of therapy remains unknown. DNA. Oral bioavailability approaches 100% but is decreased by
Several anti-HBV agents have anti-HIV activity as well, includ- food; therefore, entecavir should be taken on an empty stomach.
ing tenofovir disoproxil, tenofovir alafenamide, lamivudine, and The intracellular half-life of the active phosphorylated compound
adefovir dipivoxil. Emtricitabine, an NRTI used in HIV infection, is 15 hours and plasma half-life is prolonged at 128–149 hours,
has resulted in excellent biochemical, virologic, and histologic allowing once-daily dosing. It is excreted by the kidney, undergo-
improvement in patients with chronic HBV infection, although ing both glomerular filtration and net tubular secretion, and dos-
it is not approved for this indication. Although agents with dual age should be adjusted in the setting of renal insufficiency.
HBV and HIV activity are particularly useful as part of a first- Suppression of HBV DNA levels was greater with entecavir
line regimen in co-infected patients, it is important to note that than with lamivudine or adefovir in comparative trials. Entecavir
acute exacerbation of hepatitis may occur upon discontinuation appears to have a higher barrier to the emergence of resistance
or interruption of these agents; this may be severe or even fatal. than lamivudine. Although selection of resistant isolates with the
S202G mutation has been documented during therapy, clinical
ADEFOVIR DIPIVOXIL resistance is rare (<1% at 5 years). However, resistance is more
frequent in lamivudine-refractory patients (~ 50% at 5 years).
Entecavir has weak anti-HIV activity and can induce development
Although initially and abortively developed for treatment of HIV of the M184V variant in HBV/HIV co-infected patients, resulting
infection, adefovir dipivoxil gained approval, at lower and less in resistance to emtricitabine and lamivudine.
toxic doses, for treatment of HBV infection. Adefovir dipivoxil is Entecavir is well tolerated. Potential adverse events are headache,
the diester prodrug of adefovir, an acyclic phosphonated adenine fatigue, dizziness, nausea, and upper abdominal pain. Co-adminis-
nucleotide analog. It is phosphorylated by cellular kinases to the tration of entecavir with drugs that reduce renal function or com-
active diphosphate metabolite and then competitively inhibits HBV pete for active tubular secretion may increase serum concentrations
DNA polymerase and causes chain termination after incorporation of either entecavir or the co-administered drug. Severe lactic acidosis
into viral DNA. Adefovir is active in vitro against a wide range of was reported in a case series of entecavir; thus caution is advised
DNA and RNA viruses, including HBV, HIV, and herpesviruses. for administration in the setting of severe hepatic decompensation.
Oral bioavailability of adefovir dipivoxil is ~ 59% and is unaf-
fected by meals; it is rapidly and completely hydrolyzed to the Lung adenomas and carcinomas in mice, hepatic adenomas and
carcinomas in rats and mice, vascular tumors in mice, and brain
parent compound by intestinal and blood esterases. Protein bind- gliomas and skin fibromas in rats have been observed at varying
ing is low (<5%). The intracellular half-life of the diphosphate is exposures, although clinical relevance is unknown.
prolonged, ranging from 5 to 18 hours in various cells; this makes
once-daily dosing feasible. Adefovir is excreted by both glomerular
filtration and active tubular secretion and requires dose adjust- LAMIVUDINE
ment for renal dysfunction; however, it may be administered to
patients with decompensated liver disease. The pharmacokinetics of lamivudine are described earlier in this
Of the oral agents, adefovir may be slower to suppress HBV
DNA levels and the least likely to induce HBeAg seroconversion. chapter (see Nucleoside and Nucleotide Reverse Transcriptase
Inhibitors). The more prolonged intracellular half-life in HBV-
Emergence of resistance is up to 29% after 5 years of use. How- infected cell lines (17–19 hours) than in HIV-infected cell lines
ever, there is no cross-resistance between adefovir and lamivudine (10.5–15.5 hours) allows for lower doses and less frequent admin-
or entecavir. istration. Lamivudine can be safely administered to patients with
Adefovir is well tolerated at doses used to treat HBV infec-
tion. A reversible increase in serum creatinine has been reported decompensated liver disease. Prolonged treatment has been shown
to decrease clinical progression of HBV, as well as development of
in 3–9% of patients after 4–5 years of treatment. Other potential hepatocellular cancer by approximately 50%. Also, lamivudine has
adverse effects are headache, diarrhea, asthenia, and abdominal been effective in preventing vertical transmission of HBV from
pain. As with other NRTI agents, lactic acidosis and hepatic ste- mother to newborn when given in the last 4 weeks of gestation.
atosis are a risk owing to mitochondrial dysfunction. Pivalic acid, Lamivudine inhibits HBV DNA polymerase and HIV reverse
a by-product of adefovir metabolism, can esterify free carnitine transcriptase by competing with deoxycytidine triphosphate for
and result in decreased carnitine levels. However, it is not neces- incorporation into the viral DNA, resulting in chain termination.
sary to administer carnitine supplementation with the low doses Although lamivudine results in rapid and potent virus suppres-
used to treat patients with HBV (10 mg/d). Adefovir is embryo- sion, chronic therapy is limited by the emergence of lamivudine-
toxic in rats at high doses and is genotoxic in preclinical studies.
resistant HBV isolates (eg, L180M or M204I/V), estimated to
occur in 15–30% of patients at 1 year and in up to 65% after
ENTECAVIR 5 years of therapy. Resistance has been associated with flares of
hepatitis and progressive liver disease. Cross-resistance between
Entecavir is an orally administered cyclopentyl guanosine nucleo- lamivudine and emtricitabine or entecavir may occur; however,
side analog that competitively inhibits all three functions of HBV adefovir and tenofovir maintain activity against lamivudine-
DNA polymerase, including base priming, reverse transcription of resistant strains of HBV.