Nucleotide analogue prodrug tenofovir disoproxil enhances lymphoid cell loading following oral administration in monkeys

Abstract

The antiviral drug tenofovir (TFV) is orally administered as the fumarate salt of its disoproxil prodrug (TFV disoproxil fumarate (TDF)). TFV is a dianion at physiological pH and, as a result, has poor lipid membrane permeability. Administration of the lipophilic and cell-permeable prodrug, TFV disoproxil, enhances the oral absorption of TFV. In order to determine whether oral administration of TDF also increases distribution to sites of viral infection, the plasma and circulating lymphoid cell pharmacokinetics of TFV and its phosphorylated metabolites were assessed following a single oral TDF or subcutaneous TFV administration at doses yielding equivalent plasma exposures to TFV in macaques. Despite TFV disoproxil's lack of plasma stability and undetectable levels in the first plasma samples taken, oral administration of TDF resulted in 7.9-fold higher peripheral blood mononuclear cell exposures to the active metabolite, TFV-diphosphate. The apparent plasma terminal half-life (t(1/2)) of TFV was also longer following oral TDF relative to subcutaneous TFV administration (median t(1/2) of 15.3 and 3.9 h, respectively), suggesting broader distribution to cells and tissues outside of the central plasma compartment. In conclusion, the disoproxil pro-moiety enhances not only the oral absorption of TFV but also tissue and lymphoid cell loading. These results illustrate that administration of even a fleeting prodrug can increase target tissue loading and give valuable insight for future prodrug development.

Figure 1

Structure of TFV and the fumarate salt of its orally bioavailable disoproxil prodrug (TDF).

Figure 2

Pharmacokinetic profiles of TFV in plasma following a single administration of either 4 mg/kg subcutaneous TFV (filled circles) or 30 mg/kg oral TDF (open circles) to macaques. Values represent the median (minimum-maximum) of 5 monkeys dosed with each regimen in a sequential study design with a 6 week washout period.

Figure 3

Pharmacokinetic profiles of TFV (A), TFV-MP (B) and TFV-DP (C) in PBMC following a single administration of either 4 mg/kg subcutaneous TFV (filled circles) or 30 mg/kg oral TDF (open circles) to macaques. Values represent the median (minimum-maximum) of 5 monkeys dosed with each regimen in a sequential study design with a 6 week washout period.

Figure 4

Intracellular levels of the endogenous nucleotides dATP (A) and dGTP (B) in PBMC following administration of either 4 mg/kg subcutaneous TFV (filled circles) or 30 mg/kg oral TDF (open circles) to macaques. Values represent the median (minimum-maximum) of 5 monkeys dosed once with each regimen in a sequential study design with a 6 week washout period.