HIV Pharmacology Workshop: Explaining tenofovir renal toxicities and interactions with protease inhibitors

Interactions between tenofovir and protease inhibitors appear to be governed by a wider range of drug transporters than previously assumed, according to findings presented at the HIV Pharmacology Workshop in Lisbon, suggesting that drug interaction studies involving tenofovir will be essential in the development of all new protease inhibitors.

As the newest nucleotide reverse transcriptase inhibitor (NtRTI), there is still a need to understand better the pharmacokinetic profile of tenofovir including intestinal absorption, potential for renal drug interactions and impact on co-administered protease inhibitors (PIs).

The prodrug form of tenofovir (tenofovir disoproxil fumarate) is delivered through the gut wall. Tenofovir is cleared through the kidneys, but renal elimination of tenofovir has shown to be affected by other drugs that are also renally excreted. The level of reduction in tenofovir clearance directly correlates with nephrotoxic effects.

Notably, coadministration of tenofovir with some protease inhibitors, such as atazanavir and lopinavir, results in elevated tenofovir levels.

The interaction between PIs and tenofovir has been hypothesised to occur on the basis that some drug transporters mediated by PIs may affect tenofovir renal efflux, causing an accumulation of tenofovir in proximal tubule cells leading to nephrotoxic events.

This means that some PIs are effluxed out of the kidneys by the use of specific drug transporters such as P-glycoprotein (Pgp) or MRP2 or MRP4 – the drug transporters most frequently associated with drug trafficking in and out of the kidney cells.

A study by scientists at Gilead demonstrated in vitro which drug transporters may be responsible for drug-drug interactions between tenofovir and atazanavir, lopinavir and ritonavir. They found that Pgp and MRP2 are not substrates of tenofovir, but they did observe that tenofovir metabolites accumulated at fivefold lower levels in MRP4 over-expressing cells. The researchers did not correlate intracellular levels with cytotoxicity in MRP4 over-expressing cells.

These results confound other studies that link tenofovir with nephrotoxicity as a result of interaction between tenofovir and PIs in over-expressing MRP2 kidney cells. This is a surprising result, since according to Gilead scientists, MRP2 over-expressing cells should have a minimal impact on possible interactions between TDF and PIs, given that MRP4 has been identified as the primary transporter of tenofovir out of the kidneys.

One such study linking MRP2 to tenofovir was the brecanavir/ritonavir interaction study presented by GlaxoSmithKline (GSK). Brecanavir/ritonavir is the new GSK PI boosted with low dose ritonavir for treatment in PI-experienced patients. Ritonavir co-administered with other PIs is known to increase plasma concentration of TDF and ritonavir is responsible for the inhibition of the MRP2 transporter. In this healthy adult study 15 individuals were randomised to an open-label cross-over study to receive TDF 300mg QD for seven days followed by brecanavir/ritonavir 300/100mg BID plus TDF QD for another 14 days with no washout periods in between. Blood and urine sampling took place at both time points. TDF excretion, renal and creatinine clearance were monitored.

Results following brecanavir/ritonavir 300/100mg BID (q12hrs) combined with TDF 300mg QD (24 hours) relative to TDF QD:

These results are similar to those reported with concomitant use of other PIs including atazanavir (with or without RTV boosting) or LPV/r where 30% increases in plasma exposure of TFV were reported.