Evaluation of the Effect of Cobicistat on theIn VitroRenal Transport and Cytotoxicity Potential of Tenofovir

Abstract

A once-daily single-tablet antiretroviral regimen containing tenofovir (TFV) disoproxil fumarate, emtricitabine (FTC), elvitegravir (EVG), and cobicistat (COBI) is an approved combination for the treatment of patients infected with HIV. COBI and TFV have been reported to interact with distinct transporters in renal proximal tubules; while TFV is renally eliminated by a combination of glomerular filtration and tubular secretion via anion transporters OAT1, OAT3, and MRP4, COBI inhibits renal cation transporters, particularly MATE1, resulting in a measurable decrease in the tubular secretion of creatinine. To investigate the potential for a renal drug-drug interaction between TFV and COBI in vitro, the uptake of TFV in the presence and absence of COBI was determined in fresh human renal cortex tissue and in cells expressing the relevant renal transporters. At concentrations exceeding clinical protein-unbound plasma levels, COBI did not significantly inhibit the transport of TFV by the anion transporters OAT1, OAT3, and MRP4 (50% inhibitory concentrations [IC 50 s] of >15, 6.6, and 8.5 M, respectively). Conversely, TFV had little or no effect on the cation transporters OCT2 and MATE1 (IC 50 > 100 M). Consistent with studies using individual transporters, no increase in the accumulation of TFV in freshly isolated human renal cortex tissue or renal proximal tubule cells (RPTECs) was observed in the presence of COBI. Finally, COBI alone or in combination with FTC and EVG did not affect the sensitivity to TFV of cultured primary RPTECs or cells coexpressing OAT1 and MRP4. These results illustrate that COBI and TFV interact primarily with distinct renal transporters and indicate a low potential for pharmacokinetic renal drug-drug interaction. STRIBILD, an antiretroviral single-tablet regimen, consists of two nucleoside/nucleotide HIV reverse transcriptase inhibitors, tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine, combined with the integrase strand transfer inhibitor elvitegravir and the pharmacokinetic enhancer cobicistat (COBI), which effectively blocks the CYP450-mediated metabolic clearance of elvitegravir (1-4). Once-daily treatment with this regimen showed noninferior and durable efficacy and safety in treatmentnaive HIV-infected patients when compared head-to-head with either efavirenz (5, 6)-or atazanavir (7-9)-containing once-daily treatment regimens. A small, early, and nonprogressive increase in the levels of serum creatinine due to a COBI-mediated blockade of creatinine active tubular secretion without an effect on glomerular filtration or overall renal function has been observed during clinical trials (10).The orally administered prodrug TDF is unstable in plasma and is rapidly hydrolyzed, releasing the parent nucleotide TFV. TFV is renally eliminated by a combination of glomerular filtration and active tubular secretion via renal transporters (11-15). TFV is taken up into proximal tubules by renal organic anion transporter 1 (OAT1) and OAT3, and its luminal efflux is mediated by ABC efflux pum...

HIV integrase inhibitors: a new era in the treatment of HIV

“…This recommendation is only made in the case of COBI alone (Tybost Ò ) 'if any coadministered agent (e.g., FTC,3TC,TDF, or adefovir) requires dose adjustment based on creatinine clearance' [46]. All of these are in spite of the fact that the potential for renal drug-drug interactions between COBI and TDF appears to be low, with in vitro and ex vivo data suggesting that the transport mechanisms known to be responsible for the tubular secretion of TDF may be minimally affected by COBI under pharmacologically relevant conditions and tenofovir may have little (if any) effect on MATE-1 or OCT2 [47,48]. DGV, which is considered a second-generation INSTI, may be the most 'complete' drug in its class.…”

Darunavir/cobicistat once daily for the treatment of HIV

“…Cobicistat increases plasma tenofovir exposure when co-administered with the prodrug tenofovir disoproxil fumarate. This is not considered clinically relevant, and the potential for a pharmacokinetic renal drug-drug interaction is low as both drugs interact primarily with distinct renal transporters, and cobicistat does not interfere with the active renal tubular secretion of tenofovir [42,43]. Cobicistat increased digoxin maximum plasma concentration (C max ) by 41% and exposure (area under the plasma concentrationtime curve [AUC]) by 20% [44].…”

Profile of once-daily darunavir/cobicistat fixed-dose combination for the treatment of HIV/AIDS

“…For this reason, an increase of 0.05–0.1 mg/dL in plasma creatinine concentrations and a decrease of ~10 mL/min in eGFR CG are expected at week 4 after cobicistat is started. This variation remains stable during treatment with cobicistat and reverts once it is discontinued 21. However, clearance remains unaffected20 when GFR is calculated using standardized methods to assess actual (rather than estimated) clearance, such as iohexol, a substance not secreted or reabsorbed by renal tubule 22.…”

“…It is worth noting that cobicistat inhibits tubular creatinine secretion, which disturbs renal function estimation without affecting the real glomerular function 21. However, there are several other antiretroviral drugs with a similar effect, such as ritonavir, rilpivirine and dolutegravir, which may also increase plasma creatinine levels due to MATE1 inhibition in the renal tubular cell 36.…”