Previous evaluations of the pharmacokinetics of EFV and LPV/RTV in hemodialysis have relied on single case studies or small series. For instance, Izzedine et al. suggested that EFV dosing may need to be increased in the hemodialysis population as the drug levels in a single subject were lower than those reported for normal subjects [16
]. However, the HIV-1 viral load was <200copies/mL after 6 months of therapy in this subject suggesting that virologic efficacy at the usual dose was not compromised. In a case series of two subjects, Das reported that the projected 10-hour trough levels were in the therapeutic range in one subject but was below this target in another [17
]. However, the HIV-1 RNA levels were below 50 copies/mL, which suggested good virologic control at standard dosing.
Our data do not suggest lower concentrations of EFV in HIV-infected subjects receiving hemodialysis. Rather, bioequivalence using no-effect boundaries of 50–200% was observed for Cmax and AUC, but not for Cmin, when compared to historical controls. There was a trend toward increased Cmin, Cmax, and AUC in the hemodialysis group with higher than expected coefficients of variation. This result is likely due to known effects of polymorphisms of the CYP2B6 gene on the disposition of EFV. Similar to other studies [8
], higher EFV AUC, Cmin, and Cmax were observed in the two subjects with the TT polymorphism of the CYP2B6 516 codon compared to the four subjects with the GG genotype. Because HIV-infected African-Americans are more likely to require hemodialysis [19
] and are also more likely to carry the TT genotype compared to European-Americans and Hispanics [8
], increases in EFV drug concentrations are not unexpected in the HIV-infected hemodialysis population. The frequency rate of the TT genotype in our study (18%) is similar to that found in the general Black population (17%) [8
], so it is unlikely that a selection bias for this genotype occurred in our study. Although others have reported an association between higher EFV concentrations with more severe side effects [20
], we did not find any relationships between EFV levels and adverse signs, symptoms, or laboratory parameters. However, as only medically stable subjects without severe symptoms were enrolled, our ability to correlate pharmacokinetic parameters with adverse events was limited. We also did not find any correlations between EFV levels and either CD4 cell count or HIV-1 RNA level, which is in agreement with most [8
], but not all [24
], studies in subjects without renal failure.
Overall, the PK parameters for LPV in the hemodialysis subjects in this study suggest a potentially lower systemic exposure in this group. Even though the confidence intervals for the LPV AUC and Cmax geometric mean ratios were within the no-effect boundaries of 50%–200%, the confidence interval for the LPV AUC ratio did not include 100%. Using NEB of 80%–125%, Cmin in the hemodialysis group was definitely lower compared to historical controls. To our knowledge, the only other published report of LPV pharmacokinetics in hemodialysis involved a single subject [26
]. Cmin, Cmax, and AUC were all substantially higher in this subject compared to the values found in the current study [26
], perhaps due to differences in methodologies in measurement of LPV concentrations. Interestingly, a study performed by the manufacturer of the PI atazanavir also found an unexpected reduction in pharmacokinetic parameters in hemodialysis subjects, which prompted a change in the labeling for this drug to avoid its use in treatment-experienced patients requiring hemodialysis (http://www.fda.gov/cder/foi/label/2007/021567s014lbl.pdf
On average, we found less than 1% free LPV, suggesting that protein-binding in this group is similar to that found in HIV-infected subjects with normal renal function [15
]. Thus, a reduction in protein-binding of LPV in subjects requiring hemodialysis, with subsequently greater metabolism and clearance of this drug, likely does not explain the possibly lower trough concentrations and suggests that LPV clearance by hemodialysis itself likely would not occur. It is possible that altered gastrointestinal absorption, volume of distribution, or function or regulation of hepatic metabolic enzymes for LPV may occur in severe chronic kidney disease, thereby resulting in lower trough concentrations of LPV/RTV. We did find a marginal association between lower Cmin concentrations and A→ G polymorphisms at the CYP3A5 6986 position. The homozygous GG genotype results in very low expression of CYP3A5 protein. Therefore, we would have expected to see increased concentrations of LPV with the GG genotype. Although the allelic frequency ranges for the CYP3A5 AA, AG, and GG genotypes in Blacks are estimated, respectively, to be 36–54%, 25–50%, and 3–35% [27
], which are roughly comparable to those found in this study, our findings should be interpreted with caution as only one of ten subjects was homozygous for the GG genotype. Further research is clearly needed to investigate the associations between LPV and CYP3A5 polymorphisms.
To maximize virologic efficacy and prevent resistance development, LPV concentrations considerably higher than the protein-binding corrected IC50
against HIV should be maintained throughout the dosing interval. For this reason, once daily LPV dosing, which typically results in lower Cmin values compared to twice daily dosing [28
], is not recommended for PI-experienced patients. The LPV Cmin values in the current study of hemodialysis patients are similar to those found in those receiving 800mg of LPV in those with normal renal function. Therefore, this suggests that twice daily dosing of LPV 400mg in hemodialysis would be expected to be adequate therapy in those not previously receiving PI-based therapy but perhaps not in PI-experienced patients. However, once daily dosing of LPV in a hemodialysis population may result in further decreases in Cmin, thereby possibly jeopardizing virologic efficacy even in PI-naïve patients with end stage renal disease. We studied subjects who had been receiving the capsular form of LPV/RTV, which is no longer available. It is unknown if kidney disease and the use of hemodialysis would affect the disposition of LPV or RTV when given as the tablet co-formulation.
The primary limitation to this study was the use of historical controls as opposed to concurrently enrolled subjects with normal renal function. However, the results of this study suggest that tight matching by genotype would have been required to determine the effects of renal disease alone on the pharmacokinetics of these drugs. Screening by genotype would have been overly cumbersome to perform as part of this study. We limited any systematic biases by designing protocols that were closely matched to those used in the studies chosen for comparison. These studies also included HIV-infected patients receiving the identical dose and formulation of EFV and LPV/RTV. Our studies also rigorously assessed pharmacokinetic parameters over the full dosing interval, which is especially important for EFV, in a large number of patients, which should have minimized variability. Therefore, the differences found in PK values between hemodialysis patients and those with normal renal function are likely to be accurate. Because screening logs were not kept, we cannot assess the generalizability of these results to those patients who did not meet the strict eligibility criteria of this protocol. As such, extension of our conclusions to the general HIV-infected population requiring hemodialysis may not be warranted.
In summary, these results suggest that the effects of CYP2B6 polymorphisms at position 516 on EFV pharmacokinetics may be especially important in HIV-infected hemodialysis patients as this group is disproportionately black. However, dosing of EFV in this population does not appear to require adjustment based on our results. LPV/RTV dosing also does not require adjustment if being used in PI-naïve patients, but caution should be exercised with the 400mg/100mg twice daily regimen in those who are PI-experienced. Once daily dosing of LPV/RTV may also be inadequate, even in PI-naïve patients. Further study of the LPV/RTV tablet formulation at various doses in the HIV-infected hemodialysis population is warranted.