Tenofovir plasma pharmacokinetics were well described by a two-compartment model. However, the lack of points in the absorption phase did not allow us to estimate a value for ka
. As fixing this parameter was not possible, an alternative model in which a common value was estimated for ka
and α was preferred. Our mean CL/F
estimate (90.9 liters/h) was nevertheless close to the previously reported value in healthy volunteers (88.1 liters/h) (6
). Furthermore, a pharmacokinetic study performed after intravenous administrations of tenofovir in HIV patients (5
) reported CL and Vss
values of approximately 18 liters/h and 800 liters, respectively. As tenofovir bioavailability is thought to be about 25 to 30% (1
), these results are also in agreement with our own data (i.e., 90.9 liters/h for CL/F
and 2,064 liters for Vss
). The mean calculated AUC0-24
obtained in the present study (3.0 mg · h/liter) was also similar to the previously described values (3.6 mg · h/liter) (6
), 2.94 mg · h/liter (1
). Our results also confirmed the increase in tenofovir AUC0-24
induced by concomitant treatment with lopinavir/ritonavir that has been reported previously (10
). A possible explanation for this pharmacokinetic interaction is the inhibition of the Mrp-2-mediated transport of tenofovir outside renal tubules (13
). Our data did not allow us to identify the similar interaction with atazanavir (10
) as this association involved only two patients. Didanosine was combined with tenofovir for 60 patients. If this association is known to increase didanosine exposure (10
), an effect of didanosine on tenofovir pharmacokinetics was not found in the present study.
As expected, the four patients with tubular dysfunction had markedly reduced concomitant CL/F compared to patients with equivalent CLCR values but without tubulopathy. This discrepancy between CLCR and tenofovir CL/F can be explained by the importance of tubular secretion in the renal elimination of tenofovir. For these patients, tubular dysfunction was imputed to tenofovir therapy as the renal function normalized after the tenofovir treatment was stopped.
Tenofovir is indeed known to induce tubular dysfunction that can lead to renal impairment in a limited number of patients (13
). Hypophosphatemia is a biological sign that is thought to occur in 100% of tenofovir-induced tubular dysfunction (7
). No relationship was found between phosphatemia and tenofovir CL/F
in the present study. However, this result can be explained by the fact that hypophosphatemia is a parameter of poor specificity (4
) and does not mean that this relationship does not exist in patients with tenofovir-induced tubular dysfunction. However, one interesting point that remains to be assessed is the possible relationship between a high tenofovir exposure at the beginning of tenofovir therapy and the incidence of tenofovir-induced tubulopathy.
A strong relationship was found between tenofovir CL/F
. Serum creatinine alone did not provide such an improvement of the fit, probably because it is not an accurate marker of the renal function as it does not take into account creatinine production from muscle mass, a parameter that can be reflected by body weight. The effect of CLCR
was also less pronounced, maybe because the Cockroft-Gault and Jelliffe formulas also take gender and age into account, two covariates that showed no significant effect on CL/F
. Thus, and as it was previously suggested (11
could appear as a surrogate marker of the renal function, which explains its significant effect on tenofovir CL/F
Tenofovir exposure decreased when BW/SCR
increased, the highest BW/SCR
values corresponding to an AUC0-24
markedly lower than the mean AUC0-24
reported for the recommended 300-mg TDF dose (i.e., 2.94 mg · h/liter) (1
). This decrease in tenofovir AUC0-24
could have consequences upon treatment efficacy. Indeed, the phase II study cited above (1
) demonstrated that mean viral load decrease and AUC0-24
were −1.2 log10
copies/ml and 2.94 mg · h/liter, respectively, for the 300-mg dose, whereas the mean viral load decrease and AUC0-24
were −0.44 log10
copies/ml and 1.6 mg · h/liter, respectively, for a 150-mg dose. Furthermore, another phase II study showed the existence of a correlation between tenofovir AUC0-∞
at the first day of treatment and the antiviral response at the 14th day (5
). Thus, though tenofovir is an inactive prodrug, these two studies strongly suggested the existence of a relationship between tenofovir exposure and the treatment efficacy.
Our results did not allow us to identify such a relationship. However, this does not mean that such a relationship does not exist as our study was not designed for this virological endpoint. A rigorous methodology would have necessitated virological as well as pharmacological selection criteria. Because of the lack of such criteria, many biases (i.e., unknown viral load for 114 patients, viral load at the beginning of tenofovir therapy, tenofovir therapy duration at sampling time, combined antiretroviral drugs, treatment history, compliance, etc.) can explain the lack of correlation between viral load and tenofovir AUC0-24 that we observed. In consequence, it seems important to investigate the possible influence of the renal function of patients receiving TDF at 300 mg QD on treatment efficacy in a prospective trial.
In conclusion, this study showed that tenofovir plasma clearance was related to the body weight/serum creatinine ratio and that high ratio values corresponded to an important decrease in tenofovir AUC0-24. The virological consequence of this decrease in tenofovir exposure should be prospectively investigated, and the usefulness of a dosage adjustment based on body weight/serum creatinine ratio should be evaluated in further studies.