Tenofovir pharmacokinetics

Tenofovir disoproxil fumarate 300 mg once daily modestly increased the saquinavir AUC and minimum level by 29% and 47%, respectively, after administration of saquinavir/ritonavir 1000/100 mg twice daily in healthy subjects. The only change in tenofovir pharmacokinetics was a slight 23% increase in minimum level. In another study, mentioned hy the manufacturer of saquinavir, in 18 UTV-positive patients treated with saquinavir/ritonavir 1000/100 mg twice daily and tenofovir disoproxil fumarate 300 mg once daily, saquinavir AUC and maximum values were just 1% and 7% lower, respectively, than those seen with saquinavir/ritonavir alone. 

Luber AD, Condoluci DV, Slowinski PD, Andrews M, Olson K, Peloquin CA, Pappa KA, Pakes GE COL104422 Study Team. Steady-state amprenavir and tenofovir pharmacokinetics after coadministra-tion of unboosted or ritonavir-boosted fosamprenavir with tenofovir disoproxil fumarate in healthy volunteers. HIV Med 2010 11(3) 193-9. 

Tenofovir In an open, three-period study of the interaction of tenofovir disoproxil fumarate 300 mg/day with either fosamprenavir 1400 mg bd or fosamprenavir + ritonavir 700/100 mg for 14 days in 36 healthy subjects, steady-state plasma amprenavir and tenofovir pharmacokinetics were minimally or not significantly altered [170 ]. 

The pharmacokinetics of tenofovir have not been evaluated in nonhemodialysis patients with Ccr less than 10 mL/min therefore, no dosing recommendation is available for these patients. 

Pharmacokinetics One emtricitabine/tenofovir disoproxil fumarate tablet was bioequivalent to 1 emthcitabine capsule (200 mg) plus 1 tenofovir disoproxil fumarate tablet (300 mg) following single-dose administration to fasting healthy subjects. 

Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in... 

Tenofovir disoproxil fumarate (Viread) is a prodrug of tenofovir, a phosphorylated adenosine nucleoside analogue, and is the only available agent of its class. It is converted by cellular enzymes to tenofovir diphosphate, which competes with deoxyadenosine triphosphate (dATP) for access to reverse transcriptase and causes chain termination following its incorporation. Tenofovir was approved as part of a combination therapy for HIV in adults who failed treatment with other regimens it appears to be effective against HIV strains that are resistant to NRTIs. The pharmacokinetic properties of tenofovir are provided in Table 51.2. 

Barditch-Crovo P, Decks SG, Collier A, Safrin S, Coakley DF, Miller M, Kearney BP, Coleman RL, Lamy PD, Kahn JO, McGowan I, Lietman PS. Phase Fn trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother 2001 45(10) 2733-9. 

Emtricitabine is not metabolized to a significant extent by CYPs, and it is not susceptible to any known metabolic drug interactions. The possibility of a pharmacokinetic interaction involving renal tubular secretion, such as that between trimethoprim and lamivudine, has not been investigated for emtricitabine, although the drug does not alter the pharmacokinetics of tenofovir. 

Tenofovir is not metabolized to a significant extent by CYPs and is not known to inhibit or induce these enzymes. However, tenofovir has been associated with a few potentially important pharmacokinetic drug interactions. A 300-mg dose of tenofovir increased the didanosine AUC by 44 to 60% probably as a consequence of inhibition of the enzyme purine nucleoside phosphorylase by both tenofovir and tenofovir monophosphate. These two drugs probably should not be used together, or if this is essential, the dose of didanosine should be reduced from 400 to 250 mg/day. 

Zidovudine had no effect on methadone levels in one study, but there is one report of a patient requiring a modest increase in methadone dose after starting zidovudine. Similarly case reports describe patients requiring a modest increase in methadone dose after starting abacavir. Methadone can increase zidovudine serum levels, and reduce levels of abacavir, stavudine, and didano-sine from the tablet formulation, but not the enteric-coated capsule preparation. Tenofovir, and a single dose of zidovu-dine/lamivudine had no effect on methadone pharmacokinetics. 

In a study in 13 healthy subjects receiving methadone, tenofovir 300 mg daily for 2 weeks did not alter the pharmacokinetics of methadone, and no symptoms of opioid toxicity or opioid withdrawal were detected. ... 

Smith PF, Kearney BP, Liaw S, Cloen D, Bullock JM, Haas CE, Yale K, Booker BM, Ber-enson CS, Coakley DF, Flaherty JF. Effect of tenofovir disoproxil fiimarate on the pharmacokinetics and pharmacoi Tiamics of total, R-, and S-medi ne. Phannacodienqjy (2004) 24,970-77. 

Adefovir is excreted by the kidneys, by a combination of glomerular filtration and active secretion via the rend transporter, human Organic Anion Transporter 1 (hOATl). The potential for pharmacokinetic interactions with co-trimoxazole, ibuprofen, lamivudine, paracetamol and tenofovir (other drugs that also undergo, or may affect tubular secretion) has been investigated. ... 

Kearney BP, Ramanathan S, Cheng AK, Ebrahimi R, Shah J. Systemic and renal pharmacokinetics of adefovir and tenofovir upon coadministration. J Clin Pharmacol (2005) 45,935-40. Erratum. Ibid, 1206. 

There appears to be no pharmacokinetic interaction between entecavir and adefovir, iamivudine or tenofovir. However, interactions with other renaiiy excreted drugs cannot be excluded. No interactions mediated by cytochrome P450 isoenzymes are expected with entecavir. 

Since entecavir is predominantly eliminated by the kidney, the concurrent use of drugs that reduee renal funetion or eompete for aetive tubular secretion may increase serum concentrations of either enteeavir or the concurrent drug. However, the manufaeturers note that there was no pharmacokinetic interaction between enteeavir and iamivudine, adefovir or tenofovir at steady state.They say that, apart from these drugs, the effects of concurrent use of enteeavir with drugs that are excreted renally or affect renal funetion have not been evaluated, and they therefore recommend that patients should be monitored elosely for adverse reactions when enteeavir is given. ... 

The pharmacokinetic data suggest that no maraviroc dose adjustment is likely to be needed if it is given with tenofovir or co-trimoxazole. 

In a placebo-controlled, crossover study in healthy subjects, the concurrent use of maraviroc 300 mg twice daily and tenofovir disoproxil fuma-rate 300 mg once daily had no effect on the pharmacokinetics of maraviroc. ... 

In a placebo-controlled, crossover study in healthy subjects maraviroc 300 mg twice daily had no clinically relevant effect on the pharmacokinetics of zidovudine/lamivudine (Ctmbivir) 300/150 mg twice daily, when they were given together for one week. For the effect of other NRTIs in combination with protease inhibitors or NNRTIs on maraviroc, see CYP3A4 inhibitors , (p.780) and CYP3A4 inducers , (p.780), and for the effect of tenofovir, see Drugs that affect renal clearance , (above). 

No pharmacokinetic interaction appears to occur between tenofovir and efavirenz or nevirapine. Some ciinicai data have shown a high rate of treatment faiiure when tenofovir is given with enteric-coated didanosine and either efavirenz or nevirapine. 

In a pharmacokinetic study, there was no interaction between efavirenz 600 mg daily and tenofovir disoproxil fumarate 300 mg daily.Similarly, in a retrospective analysis, plasma levels of nevirapine 200 mg twice daily or 400 mg once daily did not differ between patients taking tenofovir disoproxil fumarate 300 mg once daily and those not. Also, efavirenz plasma levels did not differ between patients taking tenofovir and patients not taking tenofovir. It appeared that neither nevirapine nor efavirenz altered tenofovir levels. ... 

Tenofovir increases the levels of didanosine an increased risk of pancreatitis and peripheral neuropathy has been reported, and a high level of treatment failure. There is no pharmacokinetic interaction between tenofovir and abacavir, emtricitabine, lamivudine or stavudine. However, the combination of tenofovir, lamivudine and abacavir was unexpectedly associated with a high level of treatment failure. Triple-NRTI regimens invoiving tenofovir are not recommended, with the possibie exception of tenofovir, lamivudine and zidovudine. 

The AUC of buffered didanosine 250 or 400 mg was increased by 44% when it was given 1 hour before tenofovir. Similarly the AUC of enteric-coated didanosine 400 mg was increased by 48% and 60% when didanosine was given 2 hours before and with tenofovir disoproxil fumarate 300 mg, respectively. The pharmacokinetics of tenofovir were unchanged. Another study found that the AUC of enteric-coated didanosine 250 mg (simultaneously or 2 hours apart, fasted or with food) was about equivalent to that seen with didanosine 400 mg alone when tenofovir was given. ... 

There was no pharmacokinetic interaction between tenofovir disoproxil fumarate 300 mg daily and emtricitabine 200 mg daily in a study in healthy subjects. UK and US guidelines (2006) for treatment of HIV in-... 

Kearney BP, Isaacson E, Sayre J, Ebrahimi R, Cheng AK. The pharmacokinetics of abacavir, a purine nucleoside analog, are not affected by tenofovir DF. Intersci CotfAntimicrob Agents... 

When atazanavir 300 mg once daily was given with ritonavir 100 mg once daily (as a pharmacokinetic booster), tenofovir disoproxil fumarate 300 mg once daily reduced the AUC of atazanavir by a similar amount (25%), but had less effect on the trough level (23% reduction), when compared with atazanavir/ritonavir alone. Similarly, the pharmacokinetics of atazanavir/ritonavir did not differ significantly between patients taking tenofovir and those not. Combined use increased the tenofovir AUC by 37% and the minimum level by 29%. - ... 

The US manufacturer notes that, in a phase 111 clinical study plasma amprenavir trough levels (derived from fosamprenavir) were similar in subjects receiving tenofovir with fosamprenavir and ritonavir to those in subjects not receiving tenofovir. Similarly, in a pharmacokinetic study in healthy subjects, tenofovir disoproxil fumarate 300 mg once daily had no significant effect on the pharmacokinetics of amprenavir after fosamprenavir/ritonavir 1400/100 mg once daily or fosamprenavir/ritonavir 1400/200 mg once daily. ... 

The manufacturer of tenofovir notes that there was no pharmacokinetic interaction betw een tenofovir disoproxil fumarate 300 mg once daily and nelfinavir 1.25 g twice daily in healthy subjects. ... 

Kurowski M, Walli R, Breske A, Kruse G, Stocker H, Banik N, Richter H, Mazur D. Coadministration of tenofovir 300 mg QD with fosamprenavir/ritonavir 1.400/100mg QD or 1.400/200mg QD does not affect amprenavir pharmacokinetics. 6 International Workdiop on Clinical Pharmacology of HIV Therapy, Quebec, 28 - 30 April, 2005. Abstract 10. Available at ... 

ChittickGE, Zong J, Blum MR, Sorbel JJ, Begley JA, AddaN, Kearney BP. Pharmacokinetics of tenofovir disoproxil fumarate and ritonavir-boosted saquinavir mesylate administered alone or in combination at steady state. Antimicrob Agents Chemo er (2006) 50,1304-10. 

Boffito M, Back D, Stainsby-Tron M, Hill A, Di Perri G, Moyle G, Nelson M, Tomkins J, Gazzard B, Pozniak A. Pharmacokinetics of s uinavir hard gel/ritonavir (1000/100 mg twice daily) when administered with tenofovir diproxil fumarate in HIV-l-infected subjects. BrJ Clin Pharmacol (2005) 59, 38 2. 

Hodder S, Bristol-Myers Squibb Company, Klein R, Struble K, FDA. Letter to health care providers. Re Important new pharmacokinetic data for REYATAZ (atazanavir sulfate) in combination with Viread (tenofovir disoproxil fumarate). August 8, 2003. Available at http //www.fda.gOv/oashi/aids/listserve/listserve2003.html (accessed 21/08/07). 

Tenofovir absorption is increased by high-fat food. Caution is recommended with drugs causing renal toxicity. Tenofovir did not alter the pharmacokinetics of ribavirin, and there was no clinically significant pharmacokinetic interaction with rifampicin (rifampin). 

Tenofovir disoproxil fumarate 300 mg daily did not alter the pharmacokinetics of a single 600-mg dose of ribavirin in 22 subjects, and the pharmacokinetics of tenofovir did not appear to be changed by ribavirin when compared with historical data. Note that, there is evidence that HIV-pos-itive patients co-infected with hepatitis C and treated with interferon alfa and ribavirin may be at increased risk of lactic acidosis and hepatic decompensation when receiving any NRTF, (p.805), including tenofovir, and increased monitoring is recommended. ... 

In 23 subjects when rifampicin 600 mg once daily was given with tenofovir disoproxil fumarate 300 mg once daily the pharmacokinetics of both drugs were not significantly changed (tenofovir compared with historical data). One subject who was withdrawn from the study had raised liver enzyme values. ... 

---