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Delavirdine

Author: Paul A. Pham, Pharm.D. and John G. Bartlett, M.D.
04-23-2008

Delavirdine not currently available in Zambia.

Zambia Information Author: Paul A. Pham, Pharm. D.

FDA

Treatment of HIV infection in combination with other antiretrovirals

brand name	preparation	manufacturer	route	form	dosage^	cost*
Rescriptor	Delavirdine (DLV)	Pfizer	oral	tablet	200 mg	$316.35 per 180
			oral	tablet	100 mg	$0.88

*Costs (rounded to the nearest dollar) are based on usual adult dosing per day, are representative of "Average Wholesale Price" (AWP), and are current within the prior three months.

^Dosage is indicated in mg unless otherwise noted.

Pill burden: 6 tabs per day (200 mg tabs)

400 mg PO tid with or without food (100mg tab should be dispersed in at least 3 oz of water before administration; 200mg tab is taken intact).
With IDV: DLV 400mg tid + IDV 600mg q8h (GI intolerance and high pill burden).
With SQV: High rates of GI intolerance and high pill burden. No data with SQV hgc; avoid use.
Not recommended with NFV, APV, and FPV.
No data with DRV/r, TPV/r, LPV/r and ATV.

DOSING FOR GLOMERULAR FILTRATION OF 50-80

400 mg tid

DOSING FOR GLOMERULAR FILTRATION OF 10-50

Usual dose.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

Usual dose.

DOSING IN HEMODIALYSIS

No data. Usual dose likely; unlikely to be removed in dialysis due to high protein binding.

DOSING IN PERITONEAL DIALYSIS

No data. Usual dose likely.

DOSING IN HEMOFILTRATION

No data. Usual dose likely.

COMMON

Rash in 18%; usually lasts 2 wks and does not require discontinuation unless desquamation or mucous membrane involvement; approximately 4% discontinue due to rash. High rates (70%) of cross-allergy between DLV and NVP [Ann Pharmacother 2000;34: 940].
Headache and fatigue (11-17%).

OCCASIONAL

Transaminase elevation in 2-5% of pts (less common and severe than with NVP).
Nausea, vomiting, diarrhea, dyspepsia, and abdominal pain.

RARE

Erythema multiforme or Stevens-Johnson syndrome.
Proteinuria.

CYP3A4 substrate and inhibitor. DLV may increase serum levels of other CYP3A4 substrates.

Drug-to-Drug Interactions

Drug-to-Drug Interaction

Drug	Effect of Interaction	Recommendations/Comments
Clarithromycin	Clarithromycin AUC: increased by 100%; 14-hydroxy clarithromycin AUC: decreased by 75%;delavirdine AUC: increased by 44%	Dose adjustment recommended with impaired renal function. Cr clearance 30-60 mL/min: 50% of clarithromycin dose. Cr clearance <30 mL/min: 25% of clarithromycin dose. Consider azithromycin.
IDV	IDV AUC: increased by 44% (compared to 800 mg q8h dose)	With co-administration, decrease indinavir to 600 mg q8h and use standard dose of DLV.
NFV	Nelfinavir AUC: increased by 72%;delavirdine AUC: decreased by 42%; Cmin: decreased by 52%	Clinical significance unknown. Alternative PI should be considered.
Rifampin	DLV AUC: decreased by 96%	Do not coadminister.
SQV	Saquinavir AUC: increased by 500%; DLV AUC: decreased by 15%	A beneficial interaction. No adjustment necessary. Use SQV 800 mg tid + DLV 400 mg tid.
ddI (buffered)	DLV AUC: decreased by 20%	Consider ddI EC or administer DLV at least 1 hr prior to buffered ddI tabs/suspension.
Alprazolam	May Increase alprazolam serum levels	Contraindicated. Consider lorazepam, oxazepam, or temazepam with DLV co-administration.
Amiodarone	May significantly increase amiodarone serum levels	Use with caution. Data limited to case report of increased amiodarone levels with IDV co-administration. Monitor for amiodarone ADR (PFTs and TSH). Consider monitoring serum levels of amiodarone. Long half-life may make titration difficult (consider alternative antiarrhythmics with cardiology consult).
Amlodipine	May increase serum level of amlodipine	Applies to all PIs and DLV: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum levels (this led to PR interval prolongation). All PIs and DLV has the potential of prolonging the PR interval with Ca channel blocker co-administration. Ca channel blockers should be started with 50% of the dose and slowly titrated with close monitoring of BP and pulse.
Amphetamine	May increase amphetamine serum levels	Clinical significance unknown. Use with caution.
Antacids	DLV AUC: decreased by 41%;decreased absorption of DLV	Clinically significant. Separate antacid dose by at least 1 hr before or 2 hrs after DLV.
APV	APV AUC: increased by 130%; DLV AUC: decreased by 61% and Cmin: decreased by 88%	Do not coadminister.
Artemether (artemisinin)	May increase serum levels of artemether	Applies to all PIs and DLV: Close monitoring for artemether toxicity (bone marrow suppression, bradycardia and seizure).
Astemizole	May significantly Increase astemizole serum levels	Contraindicated due to the potential for cardiac arrhythmias. Recommended alternative antihistamine: loratadine, fexofenadine, desloratidine, or cetirizine.
Azathioprine	Interaction unlikely	Applies to all PIs and NNRTIs: Use standard dose.
Bepridil	May significantly increase bepridil serum levels	Applies to all PIs and DLV: No data. The manufacturer of ATV, RTV, and APV does not recommend bepridil co-administration, this contraindication should extend to all PIs and DLV since a significant increase in bepridil serum levels can result in pro-arrhythmic events such as VT, PVC, and VFib.
Carbamazepine	DLV levels may be decreased and carbamazepine levels may be increased.	Co-administration not recommended. Monitor carbamazepine levels and consider TDM of PIs and NNRTI. Consider alternative agents: valproic acid, lamotrigine, levetiracetam, or topiramate.
Chlordiazepoxide	May increase serum levels of chlordiazepoxide	Applies to all PIs and DLV: Consider alternative benzodiazepines (lorazepam, temazepam, or oxazepam).
Cisapride	May significantly increase cisapride serum levels.	Contraindicated due to potential for cardiac arrhythmias. Recommended alternative: metoclopramide.
Clorazepate	May increase serum levels of clorazepate	Applies to all PIs and DLV: Consider alternative benzodiazepines (lorazepam, temazepam, or oxazepam).
Cyclophosphamide	May increase serum levels of cyclophosphamide	Applies to all PIs and DLV: Data limited to an interaction study conducted with IDV resulting in a 50% increase in cyclophosphamide serum levels. Since all PIs and DLV have the potential of increasing cyclophosphamide levels, close monitoring of cyclophosphamide-induced toxicity is recommended.
Cyclosporine	May increases serum levels cyclosporine	Monitor serum levels of cyclosporine closely with co-administration. Cyclosporine dose may need to be decreased.
Diltiazem	May increase serum levels of diltiazem	Applies to all PIs and DLV: Data limited to an interaction study conducted with ATV which resulted in doubling of diltiazem serum levels (this led to PR interval prolongation). All PIs and DLV have the potential of prolonging the PR interval with diltiazem co-administration. Diltiazem should be started with 50% of the dose and slowly titrated with close monitoring of BP and pulse.
Disopyramide	May increase disopyramide serum levels	Applies to all PIs and DLV: No data. Monitor disopyramide serum level (target: 2 to 7.5 mcg/mL).
Docetaxel	May increase serum levels of docetaxel	Applies to all PIs and DLV: No data. Close monitoring of chemotherapy-induced toxicity recommended.
Dofetilide	May significantly increase serum levels of dofetilide	Applies to all PIs and DLV: No data. Use with caution. Monitor QTc closely and adjust dofetilide dosing based on QTc prolongation and renal function. Consider an alternative class III antiarrhythmic such as bretylium or ibutilide.
Echinacea	May decrease DLV serum levels. Echinacea (400 mg 4xd) decreased CYP3A4 substrate (midazolam) by 23%.	Applies to all PIs and NNRTIs. Clinical significance unknown but should avoided until the safety of this combination is further evaluated.
Ergot Alkaloids	May significantly increase serum levels of ergotamine resulting in acute ergot toxicity	Contraindicated. Consider alternative agent for migraine such as sumatriptan (but not eletriptan since it is a CYP3A4 substrate and significant drug interaction occurred with a CYP3A4 inhibitor).
Estazolam	May increase serum levels of estazolam	Applies to all PIs and DLV: Consider an alternative benzodiazepines (lorazepam, oxazepam, or temazepam).
Ethinyl Estradiol	Ethinyl estradiol levels decreased by 20%	Clinical significance unknown. Pts should be aware of potential interaction. Alternative birth control methods should be recommended.
Ethosuximide	May increase serum levels of ethosuximide	Applies to all PIs and DLV: Consider switching to valproic acid for the treatment of absence seizure.
Etoposide	May increase serum levels of etoposide	Applies to all PIs and DLV: No data. Close monitoring of chemotherapy-induced toxicity recommended.
Felodipine	May increase serum levels of felodipine	Applies to all PIs and DLV: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum levels (this led PR interval prolongation). All PIs and DLV have the potential of prolonging PR interval with Ca channel blockers co-administration. Ca channel blockers should be started with 50% of the dose and slowly titrated with close monitoring of BP and pulse.
Fentanyl	May significantly increase serum levels of fentanyl	Use with caution. Consider morphine.
Flecainide	May increase antiarrhythmic serum levels	Applies to all PIs and DLV: Avoid co-administration; if necessary, monitor flecainide trough level with co-administration. Target: 200-1000 ng/mL. Toxicity is frequent with trough serum levels above 1000 ng/mL.
Fluconazole	No interaction	Use standard doses of both drugs.
Fluoxetine	DLV Cmin increased by 50%	Not significant. Use standard dose.
Flurazepam	May increase serum levels of flurazepam	Applies to all PIs and DLV: Consider an alternative benzodiazepines (lorazepam, oxazepam, or temazepam).
Food	DLV AUC was not affected by food	Administer DLV with or without food
Garlic supplement	No data	Studies only done with SQV resulting in SQV serum level reduction. No data with DLV. Avoid co-administration.
Granisetron	May increase serum levels of granisetron	Applies to all PIs and DLV: Consider an alternative benzodiazepines (lorazepam, oxazepam, or temazepam).
H2-blocker	May decrease DLV absorption	Contraindicated.
Heroin (Diamorphine)	Drug interaction unlikely	Interaction unlikely but illicit drug use should be avoided for obvious reasons.
Ifosphamide	May increase serum levels of ifosphamide	Applies to all PIs and DLV: No data. Close monitoring of chemotherapy-induced toxicity recommended.
Irinoteacan	May increase irinotecan serum levels	Applies to all PIs and DLV: Co-administration of ATV is contraindicated by manufacturer. All PIs and DLV also have the potential for significant interaction with irinotecan, therefore the co-administration should be done with extreme caution.
Ketoconazole	DLV Cmin: increased by 50%	No clinical data; consider dose adjustment: DLV 200-400 mg tid.
Lidocaine (systemic)	May increase lidocaine serum levels	No data. Use with caution, monitor lidocaine serum levels (target: 1.5 to 6 mcg/mL) with coadministration.
Lovastatin	May significantly increase lovastatin levels	Contraindicated. Recommended alternatives include pravastatin, rosuvastatin, or fluvastatin (and possibly atorvastatin - start at 10 mg/d). Monitor for adverse effect due to limited clinical data.
LPV	May increase LPV serum levels	Unlikely to be significant. Use standard dose for both drugs.
Mefloquine	May increase serum levels of mefloquine	Applies to all PIs and DLV: Monitor mefloquine levels. Monitor for mefloquine toxicity (dizziness, LFTs, and periodic ophthalmic examination).
Methadone	DLV AUC not affected by methadone. Methadone PK was not evaluated but DLV may have the potential for increasing methadone serum levels.	Use standard DLV dose. Monitor for sedation; methadone dose may need to be decreased.
Mexiletine	May increase antiarrhythmic serum levels	Applies to all PIs and DLV: No data. Use with caution. Monitor EKG and serum levels. Serum levels exceeding 1.5 to 2 mcg/mL have been associated with an increased risk of toxicity.
Midazolam	May significantly increase midazolam levels	Single dose IV midazolam may be used; chronic midazolam administration (oral or intravenous) should be avoided. Consider alternative benzodiazepines (lorazepam, temazepam, or oxazepam).
Milk thistle	No data	Data limited to an interaction study with milk thistle and IDV. IDV AUC unchanged; IDV Cmin decreased by 47%. Clinical significance unknown. Avoid co-administration with DLV.
Mirtazapine	May increase serum levels of mirtazapine	Applies to all PIs and DLV: Use with caution. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine.)
Mycophenolate	Interaction unlikely. No significant interaction observed with NVP.	Applies to all PIs and NNRTIs: No significant interaction observed with NVP. Use standard dose.
Nefazodone	May increase serum levels of nefazodone	Applies to all PIs and DLV: Use with caution. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine.)
Nifedipine	May increase serum levels of nifedipine	Applies to all PIs and DLV: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum levels (this led to PR interval prolongation). All PIs and DLV have the potential of prolonging the PR interval with Ca channel blockers co-administration. Ca channel blockers should be started with 50% of the dose and slowly titrated with close monitoring of BP and pulse.
Nisoldipine	May increase serum levels of nisoldipine	Applies to all PIs and DLV: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum levels (this led to PR interval prolongation). All PIs and DLV have the potential of prolonging the PR interval with Ca channel blockers co-administration. Ca channel blockers should be started with 50% of the dose and slowly titrated with close monitoring of BP and pulse.
Paclitaxel	Case reports of increased paclitaxel serum levels	Data limited to case reports of severe toxicity associated with DLV co-administration with paclitaxel. Close monitoring of paclitaxel-induced toxicity is recommended.
PCP	May significantly increase serum levels of PCP	Avoid PCP with DLV co-administration. Avoid all illicit drug use for obvious reasons.
Phenobarbital	May decrease serum level of PIs and NNRTIs. PIs and NNRTIs may increase or decrease phenobarbital serum level	Consider alternative anticonvulsants (i.e valproic acid, lamotrigine, levetiracetam, or topiramate). With co-administration, monitor anticonvulsants level and consider TDM of PIs and NNRTIs.
Phenytoin	DLV AUC: decreased by approx 90% (population PK)	Co-administration not recommended. Monitor phenytoin levels and adjust as indicated. Consider alternative agents: (i.e valproic acid, lamotrigine, levetiracetam, or topiramate).
Pimozide	May significantly increase pimozide serum levels resulting in QTc prolongation.	Contraindicated. Consider alternative: Olanzapine.
PPI (Omeprazole or pantoprazole)	May decrease DLV absorption	Co-administration is not recommended.
Propafenone	May increase propafenone serum level	Use with caution. Serum levels are not routinely recommended due to the poor correlation with efficacy and toxicity.
Quinidine	May increase quinidine levels	No data. Use with caution with close monitoring of EKG (QTc) and serum levels: Target: 2 to 5 mcg/mL.
Rifabutin	RFB AUC: increased by 100%;delavirdine AUC: decreased by 80%	Contraindicated.
Rifapentine	DLV serum levels may be significantly decreased.	Avoid co-administration.
Rosuvastatin	Other CYP3A4 inhibitor (i.e erythromycin) did not affect rosuvastatin serum levels	Interaction unlikely, but close monitoring recommended due to limited clinical data.
RTV	RTV AUC: increased by 61%; Cmin: increased by 55%. No difference in delavirdine PK parameters.	No dose adjustment necessary.
Sildenafil	May increase sildenafil serum levels	Use with caution. Do not exceed 25 mg in 48 hrs.
Simvastatin	May significantly increase simvastatin levels	Contraindicated. Consider: pravastatin, rosuvastatin or low dose atorvastatin (start with 10 mg/d).
Sirolimus	May increase serum levels of sirolimus	Dose sirolimus based on serum levels. A significantly reduction of sirolimus dose with DLV co-administration is highly likely.
St. John's wort	DLV clearance may be increased significantly	Studies only done with IDV, but St John's work likely to affect the metabolism of DLV. Do not coadminister.
Tacrolimus	May increase serum levels of tacrolimus	Dose tacrolimus based on serum levels. A significantly reduction of tacrolimus dose with DLV co-administration is highly likely.
Tadalafil	May increase serum levels of tadalafil.	Applies to all PIs and DLV: Start with 5 mg. Do not exceed 10 mg in 72 hrs. Consider sildenafil due to more clinical data and shorter half-life allowing for easier titration.
Tamoxifen	May increase serum levels of tamoxifen	Applies to All PIs and DLV: No data. Close monitoring of tamoxifen-induced toxicity recommended.
Teniposide	May increase serum levels of teniposide	Applies to all PIs and DLV: No data. Close monitoring of teniposide-induced toxicity recommended.
Terfenadine	May increase terfenadine levels	Contraindicated due to the potential for cardiac arrhythmias. Recommended alternative antihistamine: loratadine, fexofenadine, desloratidine, or cetirizine.
THC	Based on data with NFV and IDV interactions are unlikely	Applies to PIs and NNRTIs: Interactions are unlikely but illicit drug use should be avoided for obvious reasons.
Trazadone	May increase serum level of trazadone	Applies to all PIs and DLV: Use with caution. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
Triazolam	May significantly increase triazolam serum levels.	Contraindicated. Consider alternative benzodiazepines(temazepam, oxazepam, or lorazepam).
Vardenafil	May significantly increase serum levels of vardenafil.	Applies to all PIs and DLV: Do not exceed vardenafil 2.5 mg in 72 hrs (with RTV) or 2.5 mg in 24 hrs (with other PIs and DLV). Consider sildenafil due to more clinical data and less pronounced interaction. Avoid coadministration with IDV.
Verapamil	May increase serum levels of verapamil	Applies to all PIs and DLV: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum levels (this led PR interval prolongation). All PIs and DLV have the potential of prolonging PR interval with Ca channel blockers co-administration. Ca channel blockers should be started with 50% of the dose and slowly titrated with close monitoring of BP and pulse.
Vinblastine	May increase serum levels of vinblastine	Applies to all PIs and DLV: No data. Close monitoring of vinblastine induced toxicity recommended.
Vincristine	May increase serum levels of vincristine	Applies to all PIs and DLV: No data. Close monitoring of vincristine- induced toxicity recommended.
Voriconazole	May increase voriconazole AUC. Voriconazole may increase DLV AUC.	No data with DLV. Use with close monitoring.
Warfarin	May increase warfarin effects.	Other NNRTIs and PIs may also affect warfarin requirements. Monitor INR closely and adjust warfarin as indicated.

K103N; Y181C, V106M; 188L, P236L: High-level resistance.
G190A, G190S, P225H, F227L: Sensitive or even hypersusceptible (but no clinical data).

MECHANISM

Non-competitive inhibition of HIV DNA polymerase resulting in disruption of catalytic site of the enzyme.

PHARMACOKINETIC PARAMETERS

Absorption: Bioavailability 85%. Absorption highly dependent on gastric acidity.
Metabolism and Excretion: Metabolized by CYP 3A4 to several hydroxylated metabolites, which undergo subsequent glucuronidation. Both unchanged drug and metabolites are excreted in the feces.
Protein Binding: 98-99%
Cmax, Cmin, and AUC: Steady-state mean AUC=83 mcg hr/mL; Cmax=16 mcg/mL; Cmin=7 mcg/mL (400mg tid).
T1/2: 5.8 hrs

DOSING FOR DECREASED HEPATIC FUNCTION

No data. Consider dose reduction in ESLD.

PREGNANCY RISK

Category C: Placental passage of 4-15% in late-term rodent studies. Teratogenic in rodent studies resulting in ventricular septal defects. Maternal toxicity, embryotoxicity and decreased pup survival seen with doses 5x the human dose. No data on carcinogenicity.

BREAST FEEDING COMPATIBILITY

Unknown breast milk excretion. Breast feeding is not recommended in the U.S. in order to avoid post-natal transmission of HIV to the child, who may not yet be infected.

Pros: May still have activity with G190A, and G190S, P225H, F227L mutations, but little clinical data; increases drug levels of some PIs.
Cons: Low potency; less clinical data than for other NNRTIs; tid dosing.

References

Friedland GH, Pollard R, Griffith B, et al.; Efficacy and safety of delavirdine mesylate with zidovudine and didanosine compared with two-drug combinations of these agents in persons with HIV disease with CD4 counts of 100 to 500 cells/mm3 (ACTG 261). ACTG 261 Team.; J Acquir Immune Defic Syndr; 1999; Vol. 21; pp. 281-92;
ISSN: 1525-4135;
PUBMED: 10428106
Comments:Prospective randomized study comparing the following regimens: DLV + AZT + ddI; DLV + AZT; DLV + ddI; and AZT + ddI in naive pts (<6 mos of therapy). Therapy with DLV + AZT + ddI showed only modest antiviral activity and CD4 benefit compared with 2-drug regimens. VL reduction was not significantly different between AZT + ddI compared to DLV + AZT or DLV + ddI. This study is consistent with other studies showing only modest antiviral potency with DLV-containing regimens.
Para MF, Meehan P, Holden-Wiltse J, et al.; ACTG 260: a randomized, phase I-II, dose-ranging trial of the anti-human immunodeficiency virus activity of delavirdine monotherapy. The AIDS Clinical Trials Group Protocol 260 Team.; Antimicrob Agents Chemother; 1999; Vol. 43; pp. 1373-8;
ISSN: 0066-4804;
PUBMED: 10348755
Comments:Phase I-II dose-finding study. DLV monotherapy decreased VL by only 0.87-1.08 log by wk 2 (less potent than EFV or NVP). Subjects developed rapid DLV resistance.