NRTIs
Non-Nucleoside Reverse Transcriptase Inhibitors
Combivir
Other names:
AZT + 3TC
Form: 1 tablet contains 150 mg 3TC and 300 mg AZT
Dosing:
Normal: 1 tab BID
Renal failure: Do not use if CrCl
<50 ml?min
Liver failure: NA
Pediatric: NA
Food Effect: Take without regard to meals
Oral bioavailability:
Serum half-life:
Intracellular half-life:
Elimination:
Adverse Events & Toxicities: See Lamivudine and Zidovudine
FDA Pregnancy Category: Lamivudine (C); Zidovudine (C)
Combination Regimens: Combivir + ABC; Combivir + DDI
Comments:
DAPD
Other names:
Form: 25 and 100 mg tabs
Dosing:
Normal: 300-500 mg BID
Renal failure: NA, renally excreted
Liver failure: NA
Pediatric: NA
Food Effect: Take without regard to meals
Oral bioavailability:
Serum half-life:
Intracellular half-life:
Elimination:
Adverse Events & Toxicities: GI, hepatitis
FDA Pregnancy Category:
Combination Regimens:
Comments: Metabolized to dioxolane guanine (DXG) which has
an anti-HBV activity. Active against AZT-3TC, multi-NRTI resistant
HIV. Phase 3 trials, Q-day dosing under study.
Didanosine
Other names:
ddI, Videx
Form: 25, 50, 100, 150, 200, (400) mg buffered tabs; 100,
167, 250 mg/pkg power (Peds Powder Bottle) 2 g/4oz, 4g/8 oz
Dosing:
Normal: <60 kg - 250 mg QD, 125
mg BID, 167 mg pkg BID; > 60 kg - 400 mg QD, 200 mg BID, 250
mg pkg BID
Renal failure: > 50: 400 QD;
25 - 50: 200 QD; <25: 100 QD
Liver failure: Decrease dose
Pediatric: 120 mg / m2 BID
Food Effect: Levels decreased 55%; therefore, take 1/2
hour before or 1-2 hours after meals
Oral bioavailability: 30-40%
Serum half-life: 1.6 hour
Intracellular half-life: 25-40 hours
Elimination: Renal excretion 50%
Adverse Events & Toxicities: Pancreatitis, peripheral
neuropathy, nausea, diarrhea, lactic acidosis, benign hyperuricemia
FDA Pregnancy Category: B
Combination Regimens: Combivir + ABC; Combivir + DDI
Comments: For QD dosing, use Videx EC or buffered tablets,
or add 200 ml DS Mylanta to 4 g Peds powder, refrigerate up to
30 days, shake well before use. Tablets should not be swallowed
whole; must be chewed or dissolved in water or apple juice; stable
for 1 hr. in solution. Powder mixed in water should be taken immediately.
Take DDI, IDV, LPV, NFV, RTV, DLV, keto-itraconazole, dapsone
or quinolone 2 hr apart. These interactions do not occur with
VidexEC. Methadone decreases ddI-AUC in plasma by 50%, with uncertain
clinical relevance. Possible dialyzed, so take after dialysis.
DidanosineEC
Other names:
ddI-EC, Videx-EC
Form: 125, 200, 250, 400 mg caps
Dosing:
Normal: < 60: 250 QD; >60:
400 QD
Renal failure: (<60/>60) >
59: 250 /400 mg QD; 30-59: 125/200 mg QD; 10-29: 125/125; <10:
?/125
Liver failure: NA
Pediatric: NA
Food Effect: Take on an empty stomach
Oral bioavailability:
Serum half-life:
Intracellular half-life:
Elimination:
Adverse Events & Toxicities: GI, peripheral neuropathy,
pancreatitis
FDA Pregnancy Category: B
Combination Regimens:
Comments: Enteric coating protects drug from inactivation
by gastric acidity. Should not be chewed or dissolved in water;
must be swallowed whole and taken as a full dose once daily. No
significant interaction with ICV, DLV, ciprofloxacin, and ketoconazole.
Take ddI-EC and Kaletra 1-2 hrs apart. No reported interaction
with methadone. Trials have found VidexEC and ddI equally effective.
Possibly dialyzed, so take after dialysis.
Emtricitabine
Other names:
FTC, Coviracil
Form: 200 mg caps
Dosing:
Normal: 200 mg daily
Renal failure: NA (renally excreted)
Liver failure: NA
Pediatric: NA
Food Effect: Take without regard to meals
Oral bioavailability:
Serum half-life:
Intracellular half-life:
Elimination:
Adverse Events & Toxicities: Nausea, diarrhea, headache
FDA Pregnancy Category:
Combination Regimens:
Comments: Available in clinical trials only. Has anti-HBV
activity. FTC+ddI+EFV (all once daily) reported to be highly efficacious.Concerns
about hepatotoxicity, although unconfirmed, has delayed research
and development.
Lamivudine
Other names:
3TC, Epivir
Form: 150 mg, 300 mg tablets; 10 mg/ml oral solution, 240
ml bottle
Dosing:
Normal: 150 BID, 300 QD
Renal failure: 30-50: 150 mg QD;
15-29: 150X1, then 100 QD; 5-14: 150X1, then 50 QD; <5: 50
QD
Liver failure: NA
Pediatric: <1 mo: 2 mg/kg BID;
1 mo- 12 yrs: 4 mg/kg BID; >12 yrs: <50kg: 150 mg BID
Food Effect: Take without regard to meals
Oral bioavailability: 86%
Serum half-life: 3-6 hours
Intracellular half-life: 12 hours
Elimination: Renal excretion unchanged
Adverse Events & Toxicities: No significant toxicity;
peripheral neuropathy, pancreatitis
FDA Pregnancy Category: C
Combination Regimens:
3TC + AZT
3TC + d4T
3TC + AZT + ABC
Comments: Once-daily dosing approved in Europe. Liquid strawberry-banana
flavored. If not suppressed on 3TC, M184V appears swiftly and
found in early viral rebound. M184V may confer poor replicative
fitness and attenuate resistance to other NRTIs. TDF may have
increased potency in presence of M184V. Has significant anti-HBV
activity. For HD use 25 mg QD. Also part of CBV and TZV.
Stavudine-IR
Other names:
d4T, Zerit
Form: 15, 20, 30, 40 mg caps; 1 mg/ml solution in 200 ml
bottles
Dosing:
Normal: <60: 30 mg BUD; >60:
40 mg BID
Renal failure: 26-50: 50% usual,
BID; 10-25: 50% usual QD; <10: 50% usual QD
Liver failure: Probably no change
Pediatric: <30 kg: 1 mg/kg BID
Food Effect: Take without regard to meals
Oral bioavailability: 86%
Serum half-life: 1 hour
Intracellular half-life: 3.5 hours
Elimination:
Adverse Events & Toxicities: Peripheral neuropathy
FDA Pregnancy Category: C
Combination Regimens:
d4T + ddI + 3TC
(d4T + ddI ; d4T + 3TC) + PI or
NNRTI
Avoid d4T + ddC
Do not use d4T + AZT
Comments: Refrigerate solution. Probably dialyzed; take after
dialysis. Methadone decreases d4T-AUC by 27%, but with no clinically
significant events reported. Sustained release QD-tabs under study.
Activity may be decreased by concomitant Ribavirin.
Stavudine-XR
Other names:
d4T-XR, Zerit-XR
Form:80, 100 mg caps
Dosing:
Normal: <60 kg: 80 mg QD; >60:
100 mg QD
Renal failure: NA
Liver failure: Probably no change.
Pediatric: NA
Food Effect: Take without regard to meals
Oral bioavailability:
Serum half-life:
Intracellular half-life:
Elimination:
Adverse Events & Toxicities: Peripheral neuropathy
FDA Pregnancy Category: C
Combination Regimens: See stavudine
Comments: Expected in 2002. Capsule contains enteric-coated
beads of d4T, Since 20% of dose is not absorbed via large intestine,
100 QD of XR form is equivalent to 40 mg BID of regular d4T.
Tenofovir
Other names:
TDF, Viread
Form: 150, 300 mg caps
Dosing:
Normal: 300 QD
Renal failure: NA
Liver failure: NA
Pediatric: NA
Food Effect: Take with food
Oral bioavailability:
Serum half-life:
Intracellular half-life:
Elimination:
Adverse Events & Toxicities: Nausea, vomiting, diarrhea,
headaches, high LFTs and CPK
FDA Pregnancy Category: B
Combination Regimens:
Comments: Aka "PMPA." Retains activity against ADV-res,
3TC-resistant, and Q151M-containing HIV strains; activity decreases
with >3 NAMs inclusive of L210W or M41L. Increases ddI levels
by 40%. Active against HIV.
Trizivir
Other names:
TZV
Form: 1 cap contains AZT, ABC, 3TC
Dosing:
Normal: 1 tab BID
Renal failure: See AZT, ABC, 3TC.
Avoid for CrCl <50
Liver failure: See AZT, ABC, 3TC.
Pediatric: See AZT, ABC, 3TC.
Food Effect: Take without regard to meals
Oral bioavailability:
Serum half-life:
Intracellular half-life:
Elimination:
Adverse Events & Toxicities: See AZT, ABC, 3TC.
FDA Pregnancy Category: C
Combination Regimens:
Comments: Do not use in patients under 40 kg. Trizivir alone
may not be sufficient to suppress AZT- or 3TC-experienced patients.
Zalcitabine
Other names:
ddC, Hivid
Form: 0.375, 0.75 mg tablets, 0.1 mg/mL syrup
Dosing:
Normal: 0.75 mg TID (1.125 mg BID)
Renal failure: 10-40: 0.75 mg BID;
<10: 0.75 mg QD
Liver failure: Probably no change.
Pediatric: 0.01 mg/kg TID
Food Effect: Take without regard to meals
Oral bioavailability: 85%
Serum half-life:1.2 hours
Intracellular half-life: 3.5 hours
Elimination: 70% renal excretion
Adverse Events & Toxicities: Peripheral neuropathy,
stomatitis, pancreatitis.
FDA Pregnancy Category: C
Combination Regimens:
AZT + ddC
Do not use ddC with 3TC, d4T or ddI.
Comments: Antacids decrease ddC absorption. Probably dialyzed;
take after dialysis. Rarely used because of toxicty.
Zidovudine
Other names:
AZT
Form: 100 mg caps, 300 mg tabs; IV: 10 mg/ml in 20 ml vials
Dosing:
Normal: 200 mg TID; 300 mg BUD;
IV: 1 mg/kg in D5W q 4 h.
Renal failure: 10-50: 200 mg q 12H;
<10: 100 mg q 8 H or q 12h.
Liver failure: NA
Pediatric: Neonate: 2 mg/kg PO q
6h, or 1.5 mg/kg IV q 6 h for 1-3 mo; 4 mg/kg 6 6H; >3 mo:
180 mg/m2 q 6H.
Food Effect: Take without regard to meals
Oral bioavailability: 60%
Serum half-life:1.1 hours
Intracellular half-life: 3 hours
Elimination: Metabolized to AZT glucorunide (GAZT); Renal
excretion of GAZT.
Adverse Events & Toxicities: Bone marrow suppression,
anemia and/or neutropenia. Nausea, vomiting, headache, insomnia,
asthenia, myositis, neuropathy. Lactic acidosis with hepatic steatosis
is a rare but potentially life-threatening toxicity with the use
of NRTIs.
FDA Pregnancy Category: C
Combination Regimens:
AZT + ddI
AZT + ddC
AZT +3TC
AZT+3TC+ABC
Do not use AZT with d4T.
Comments: Prevention of primary AZT resistance is significant
in many areas. Antepartum, begin at 14 wks; intrapartum: 2 mg/kg
for 1 hr, then 1 mg/kg/hr until the cord is clamped. In renal
failure, use same dose at q6-8h. Activity may be decreased by
concomitant Ribavirin.
M184V mutation - Leads to high-level 3TC resistance;
also seen in many patients failing abacavir. This mutation may
be beneficial in some cases. In addition to decreasing viral fitness,
it is known to enhance the activity of adefovir and to reverse
or prevent the development of some AZT resistance mutations.
AZT / 3TC: Patients taking AZT/3TC can develop specific
mutations (eg, mutations at codons 208, 211, 214, and 333) which
render both drugs inactive.
3TC and abacavir cross-resistance: is unidirectional: abacavir
resistant virus is resistance to 3TC; but virus resistant only
to 3TC retains susceptibility to abacavir. However, ABC is generally
ineffective against virus with the M184V mutation and three or
more AZT resistance mutations.
ABC: has been shown to be ineffective as a salvage agent
in patients with extensive NRTI resistance mutations.
AZT / d4T: Recent evidence suggests that mutations typically
associated with AZT resistance can occur following failure of
d4T in AZT-naive patients. Some experts have proposed that these
mutations should be thought of as "thymidine analog mutations"
rather than "AZT resistance mutations."
Multi-drug resistance: MDR conferring cross-resistance
to the entire NRTI class is now well recognized. Multi-nucleoside
resistance genotypes include the Q151N resistance complex and
the T69SSS insertion mutation.
Non-genotypic resistance: It has been suggested that NRTIs
may sometimes fail for reasons other than genotypic resistance.
Prolonged AZT use impairs the subsequent phosphorylation of d4T,
rendering it less effective. Also, while AZT resistance mutations
may lead to a decrease in viral fitness, subsequent compensatory
mutations may actually increase viral fitness and lead to a diminished
response to other nucleoside analogs.
Thus, it is clear that second NRTI
regimens may be less reliable than initial regimens. Whether there
is a preferred order in which NRTIs should be sequenced has not
been determined.
