Clinical Pharmacology at CROI 2009: Pharmacoenhancement, Pharmacogenetics, Drug Interactions and the Pharmacotherapy of HIV Infection
Courtney V. Fletcher, Pharm.D.
Dean and Professor
College of Pharmacy
University of Nebraska Medical Center
986000 Nebraska Medical Center
Omaha, NE 68198
The 16th Conference on Retroviruses and Opportunistic Infections (CROI) was held in Montreal, Canada from February 8-11, 2009. CROI continues to be the premier HIV-focused scientific meeting. The 16th CROI had many abstracts related to clinical pharmacology. In this report I will highlight those I think are of broad interest or might benefit from some expert clarification. I will discuss abstracts in four broad categories: pharmacoenhancement, pharmacogenetics, drug interactions and the pharmacotherapy of HIV infection.
ACTG, adult AIDS clinical trials group
ARV, antiretroviral drug
ART, antiretroviral drug therapy
AUC, area under the concentration-time curve
Cmin, minimum drug concentration
CNS, central nervous system
CSF, cerebrospinal fluid
CYP, cytochrome P450 drug metabolizing enzymes
IC50, concentration of drug required to inhibit viral replication in vitro by 50%
IQ, inhibitory quotient
NRTI, nucleoside reverse transcriptase inhibitor
NNRTI, non-nucleoside reverse transcriptase inhibitor
PACTG, pediatric AIDS clinical trials group
PBMCs, peripheral blood mononuclear cells
PI, inhibitor of HIV protease
r or RTV, ritonavir
TDM, therapeutic drug monitoring
Clearly, the pharmacologic highlight of the 16th CROI were two abstracts describing the basic and ongoing clinical development of drugs that are intended to only inhibit CYP enzymes and thus be used clinically as booster for other PIs as is presently the use of RTV.
Abstract #40 described compound GS-9350 under development by Gilead Sciences. In vitro this agent demonstrated potent inhibition of CYP, no antiviral activity against HIV, and reduced in vitro effects on adipocytes. An important clinical proof of concept demonstration was evidence that GS-9350 doses of 100 and 200 mg exhibited similar and near total inhibition of the clearance of midazolam (a pure CYP substrate and thus an important marker of the ability to boost drug concentrations) as did a dose of 100 mg of RTV. Additionally GS-9350 has biopharmaceutical characteristics that are favorable for coformulation. Indeed, human bioavailability data were presented on a single tablet formulated to contain elvitegravir, GS-9350, TDV and FTC. This "quad" tablet formulation produced similar concentrations of elvitegravir (an investigational integrase inhibitor) as did the combination of elvitegravir and ritonavir. Representatives from Gilead Sciences stated during the presentation that they were interested in other coformulation opportunities - a most welcome statement.
SPI-452 was the second of the CYP inhibitors to be presented at CROI (abstract 41). This agent is being developed by Sequoia Pharmaceuticals, and like GS-9350 is a potent inhibitor of CYP. Dose ranging PK studies were conducted and subsequently combination PK studies in humans with SPI-452 at doses of 50 mg and 200 mg with SQV, ATV and DRV were performed. The ability of SPI-452 to boost these PIs was clearly demonstrated and 15-day safety and tolerance was good. No data were presented comparing the boosting ability of SPI-452 vs. RTV, and this will be necessary to see. Nonetheless, SPI-452 certainly demonstrated the ability to act as a pharmacoenhancer.
The clinical development of GS-9350 and SPI-452 are moving forward. There will need to be clear demonstrations of the long-term safety, tolerability and efficacy of these drugs as boosters. The regulatory requirements, as based on comments made at CROI, appear to require a 48-week study at the intended dose in naive patients or a 24-week study in treatment experienced patients. Time will tell whether these two drugs actually reach the market. However, there now is a clear path for the development of drugs that are as potent inhibitors of CYP as is RTV, may have fewer effects on adipocytes and therefore be more lipid friendly than RTV, pharmaceutical characteristics that allow coformulation with other agents, and manufacturers that will seek coformulation opportunities outside of their own agents. These are significant developments and real progress in the treatment of HIV infection.
II. Pharmacokinetics and Pharmacogenetics
CROI has provided an important venue for information related to the contribution of naturally occurring genetic variability to the variability seen in the PK of ARVs among patients and the variability seen in the response (pharmacodynamics, PD) to ARV therapy. I'll highlight some of the abstracts that presented PK information with clinical implications.
Abstract #939 presented PK data on single dose TDF when given to HIV-infected pregnant women during active labor and their newborns. A previous report from this PACTG study group (protocol 394) reported that a single dose of 600 mg of TDF (twice the usual single dose) to pregnant women produced concentrations less than those seen with the usual 300 mg dose. In the work presented at the 16th CROI, the study group increased the dose to the pregnant mother during active labor to a single dose of 900 mg TDF given either with 600 mg FTC or without; the newborn was given a dose of 4 mg/kg of TDF and 3 mg/kg of FTC. The PK of TDF in mother were similar whether TDF was given with or without FTC. The TDF AUC was 2519 ng*h/mL and C24 (concentration at 24 hours) was 53 ng/mL. Compared with the values these authors presented at CROI 2006, there is no real difference between the AUC and C24 values. TDF Cmax values were increased 83% with the 900 mg dose compared with the 600 mg dose. TDF cord blood concentrations averaged 68 ng/mL as was above the investigator-selected threshold of 50 ng/mL in 10 of 15 mothers. The TDF dose in newborns produced TDF concentrations quite less than exposures seen in adults. No maternal or infant adverse effects were observed. These data were largely on agreement with the findings from abstract #940, which evaluated a lower 600 mg dose of TDF in pregnant women but the same TDF dose to the newborn. Women in the #940 abstract were enrolled from Brazil and Malawi. Interestingly, PK following the 600 mg TDF dose looked more comparable to those in non-pregnant adults, however, no trough concentration information was reported. The #940 authors stated a cohort was being studied with the 900 mg dose to the pregnant women and a higher dose of 6 mg/kg to the newborn. Collectively, these data do not convince me that a dose of TDF can be recommended at this time that can be given to the pregnant woman during labor and to her newborn that will achieve plasma concentrations similar to those in non-pregnant adults. Finding the right dose can be hard and frustrating. More work, I believe is necessary.
Steve Taylor and colleagues in abstract #694 presented a pharmacologic evaluation of a clinically relevant question, how to switch patients from EFV to NVP. The issues underlying this question are whether NVP should be started at the recommended once daily dose for 14 days and then increased to twice daily, or whether because of the enzyme inducing properties of EFV, should NVP be started at the full twice-daily dose. There is uncertainty about both approaches and whether patients are exposed to period of low NNRTI concentrations and emergence of resistant isolates. These investigators evaluated a third option of co-dosing EFV and NVP for 2 weeks, with NVP being dose at 200 mg once daily for 2 weeks. At the end of 2 weeks, EFV was stopped and NVP was increased to 200 mg twice daily. In this evaluation of 13 HIV-infected persons switching from EFV to NVP primarily for CNS adverse effects, EFV concentrations were not different with NVP co-dosing. NVP concentrations with once daily administration during co-dosing, as expected, were less than the target trough concentration threshold of 3000 ng/mL. Upon the increase of the NVP dose to 200 mg twice daily and the discontinuation of the EFV, NVP concentrations when measured 2 weeks later were > 3000 ng/mL in 10 of the 13 patients (median of 4357 ng/mL). This strategy was well tolerated. There were no significant elevations in liver function tests and no patient developed a rash. These data are supportive of this third strategy to switch patients from EFV to NVP. However, all of these strategies suffer from the small number of patients evaluated. Larger PK, safety and virologic assessments of one or more of these strategies are needed.
Two important abstracts related to drug penetration into the CSF and the virologic consequences of that penetration were 702 and 484b. Both of these abstracts were from the CHARTER Group who has been at the forefront of advancing our knowledge in both of these areas. Abstract 702 examined the penetration of EFV and FTC into the CSF. Because of the CNS adverse effects of EFV we have known that it had to penetrate the CSF, but the amount has been uncertain. CSF samples were obtained from 77 patients. The median CSF concentration was 13 ng/mL and the ratio to paired plasma concentrations was 0.5%. This ratio corresponds nicely to the free (or unbound) fraction of EFV in plasma. FTC CSF concentrations were evaluated in 21 participants. The median CSF concentration was 109 ng/mL and the CSF to plasma ratio was 43%. For both EFV and FTC, the median CSF concentrations were above the IC50, suggesting the possibility of anti-HIV effect. Abstract 484b examined the question of whether low levels of HIV in the CSF were associated with differences in ART and neuropsychological performance. 300 participants in the CHARTER cohort were analyzed. All had HIV RNA in plasma < 50 copies/mL. 41% were found to have detectable HIV RNA in the CSF. Detectable HIV in the CSF was associated with a lower CSF penetration score for the ART regimen. Neuropsychological performance was poorer in those patients who had detectable HIV RNA in the CSF but not in the plasma (using an Ultrasensitive method) compared with those who had detectable HIV RNA in both compartments. This finding suggests that cognitive impairment might arise from an ART regimen with poorer CSF penetrating qualities. These data add to our knowledge of the different degrees to which ARVs penetrate the CSF, and indicate that the overall CSF penetrating characteristics of an ARV regimen seems is associated with HIV RNA in the CSF. This underscores the need for clinicians to particularly consider the CSF penetration of an ARV regimen in patients with neurocognitive impairment, but perhaps more broadly.
Pharmacogenomics. The field of pharmacogenetics (PG) is concerned with the contribution of naturally occurring genetic variability to the variability seen among patients in the PK of ARVs and the variability seen in the response (or PD) to ARV therapy. This year I thought the best of these PG studies was an investigation of the predictors of nephrotoxicity in patients treated with TDF. First, abstract 743 from the Swiss Cohort Study, sets the stage for the risk of renal dysfunction in patients receiving TDF. A cross-sectional analysis of renal function was performed in 1202 consecutive HIV-infected patients. These investigators reported that the prevalence of proximal renal tubular dysfunction was higher in TDF-treated patients and highest in those treated with both TDF and a PI. The rates of proximal tubular dysfunction were: ART-naive, 0%; no TDF or PI, 1.8%; no TDF but receiving a PI, 3.6%; receiving TDF but not a PI, 5%; and receiving both TDF and a PI, 11.5%.
Detailed laboratory and genetic evaluations were conducted on 115 HIV-infected persons; 19 had renal dysfunction and 96 had normal kidney tubular function (abstract 37). The following characteristics were associated with reduced kidney function: older age (> 60 years); reduced body weight; and a natural genetic variation in the membrane transporter ABCC2. Those individuals who had this genetic variation were 5 times more likely to develop renal dysfunction while taking TDF. Other studies have found this variant transporter present in a higher percentage of patients who developed tenofovir-induced renal proximal tubulopathy compared with patients who did not, and that those who have this variant form excrete more TDF into their urine. All is not clear with these relationships, however, as in vitro studies do not show that TDF is a substrate for this transporter. Nonetheless, this study provides direction for future investigations to elucidate the contribution of clinical characteristics and drug transporter genotype to the renal safety and efficacy of TDF, and by extension to other ARVs. The potential implications of this work are captured by the link between the HLA-B*5701 polymorphism and ABC hypersensitivity, where prospective genetic screening can reduce the toxicity associated with this drug by screening out those patients who are at higher risk from receiving ABC. This illustrates the goals of the emerging modern era of personalized medicine.
III. Drug Interactions
The study of interactions among ARV drugs, and among ARVs and other commonly used drugs remains an area of considerable study. Primarily, these interactions arise because of the concomitant use of drugs that are substrates, inhibitors and inducers of drug metabolizing enzymes, especially those of the cytochrome P450 system (CYP), and drug transporters.
Abstract #697 reminds us that one dose doesn't fit all - from a drug interaction perspective. In this study a 50 mg boosting dose of RTV was studied with SQV in Thai HIV-infected patients. 20 Thai patients receiving SQV/RTV, 1500/100 mg once daily and who had HIV RNA < 50 copies/mL had their dose of RTV reduced to 50 mg once daily. The liquid formulation of RTV was used to administer the 50 mg RTV dose. The median SQV Cmin was 130 ng/mL at baseline, and was 160 ng/mL 7 days after the RTV dose reduction. Overall, there was no difference in SQV PK with the 100 mg and 50 mg RTV dose. These data tell us that in these patients the 50 mg RTV dose was as effective at boosting SQV concentrations as was a 100 mg dose. RTV use even in boosting doses is associated with adverse effects, and it is conceivable that a lower dose may reduce the frequency. It can't be extrapolated from these data in 20 Thai patients, however, that a reduced dose of RTV will work for all patients and for all PIs that are boosted with RTV. Each setting will need careful PK, safety and virologic study, and the present liquid formulation presents limitations to do this. Abbott submitted the new Meltrex formulation of RTV for FDA approval early in 2009. If approved it is expected to be available as a 100 mg tablet, which doesn't solve all of the challenges to further study of this strategy. The ideal situation would be a 50 mg meltrex tablet or a generic, but I am not aware of what the likelihood of either of these is.
A study from South Africa (abstract #98) evaluated the use of double dose (that is, twice the usual dose) of LPV/r in children who were also receiving a rifampin based TB regimen. LPV/r PK were evaluated in 15 children older than 6 months and compared with those from 24 children without TB. LPV pre-dose (trough) concentrations were 0.63 mg/L in the LPV/r + rifampin group vs. 4.25 mg/L in the control; LPV AUC values were 22.9 mg*h/L vs. 48.33 mg*h/L in these same groups, respectively. Despite doubling the dose of both LPV and RTV, the concentrations of LPV were still significantly reduced in the presence of rifampin, and below those associated with an optimal virologic response. This strategy does not work and should not be used. No approach to date has shown the interaction between rifampin and PIs, including RTV boosted regimens, can be managed. The combination of PIs and rifampin in addition to placing patients at high risk of virologic failure can also be associated with significant hepatotoxicity. There remains a real unmet need for effective strategies for concomitant treatment of TB and HIV.
The PK and safety of twice daily RAL and twice daily ATV were evaluated in 22 healthy subjects (abstract #696). This combination is of interest because of possibilities for a two-way beneficial drug interaction that might allow a RTV-sparing regimen with both drugs being given twice daily, which might subsequently lead to coformulation possibilities. In this study the usual dose of RAL, 400 mg twice daily was used, and the dose of ATV was 300 mg twice daily (again, no RTV). The RAL AUC and Cmin were increased 54% and 48%, respectively, when given with twice daily ATV. These increases are similar to what is seen when RAL is given with once daily ATV. The mean ATV Cmin with twice daily dosing was 817 ng/mL (range, 250 to 1550 ng/mL). The level is somewhat lower than that seen with ATV/RTV of 1227 ng/mL, also in healthy volunteers (ATV package insert). When compared with ATV twice daily without RAL, the Cmin was reduced approximately 29%. The rates of hyperbilirubinemia were comparable with those of ATV+RTV. However, there were higher rates of electrocardiograph (ECG or EKG) changes with the twice-daily ATV regimen (with or without RAL): PR increase and QRS widening. The PK characteristics of the RAL and ATV twice daily of each regimen look promising. While ATV concentrations would appear to be lower than those of ATV/RTV there would be higher than those of ATV only. The clinical significance of the ECG changes will require careful study. At this time, the twice-daily regimen of RAL and ATV should only be used in carefully controlled clinical trials.
IV. Pharmacotherapy of HIV Infection
In this final category I will discuss abstracts that present information relevant to improving the safe and effective use of drugs in the treatment of HIV infection. I will primarily focus on abstracts that present pharmacologic information - that is pharmacokinetic, pharmacodynamic or pharmacogenetic data and the implications of those data to increase the likelihood of the desired response to drug therapy and minimize the risk of adverse drug effects.
Complications of ARV Use. The issue of the use of antiretroviral agents increasing the risk of myocardial infarction (MI) received considerable attention this year as it did at CROI last year. The D:A:D Study group provided an update of their investigations of the risk of MI and ARV exposure (abstract #44LB). Important was that they only evaluated risk if there was more than 30,000 person-years of exposure. Among the NRTIs, recent use (current or in the last 6 months) of ABC and ddI were associated with a significant risk of MI. Cumulative use of ABC was found to have a borderline increased risk of MI. No statistically significant association was found for recent or cumulative use of TDF, 3TC and ZDV, and none was seen for the NNRTIs EFV and NVP. Cumulative, but not recent use of IDV and LPV/r was associated with a significant risk of MI.
The risk of ARV use and MI was also reported from an analysis of the French Hospital Database on HIV (FHDH) in abstract 43LB. In this case-control analysis, only recent use of ABC was associated with an increased risk of MI. The finding of no increased risk with cumulative use of ABC differs slightly from what was found in the D:A:D analysis. Cumulative exposure to LPV/r, APV and fAPV were associated with an increased risk of MI.
The slides from both of these presentations are can be found in this link on the NATAP website.
3 Studies on Abacavir & MI Risk: French Cohort, D.A.D. (slides), ALLRT with 2 Different Results - (02/12/09)
No Association of Abacavir (ABC) Use with Risk of Myocardial Infarction (MI) or Severe Cardiovascular Disease Events (SCVD): Results from ACTG A5001/ALLRT - (02/25/09)
Collectively, these two analyses indicate certain ARVs have been found to be are associated with an increased risk of MI in these 2 cohort studies. However, these findings have not been uniform (see for example abstract 732 from the ACTG ALLRT database) and abstracts 150LB and 732 also at the 16th CROI found that ABC use was not associated with elevated markers of inflammation and endothelial activation. Thus, controversy and uncertainty exists. What is clear is the need for long-term safety data for all ARVs. This need is heightened for those where MI risk associations were found in these observational studies. Additionally and of equal importance, the pharmacologic mechanism by which any of these drugs actually cause an increased risk of MI needs prompt study and identification. With specific regard to ABC, in my opinion at this time, the DHHS Guidelines Panel recommendation that ABC/3TC should be used with caution in persons at higher risk for cardiovascular disease, was reinforced, albeit with some caveats, at this meeting and continues to be appropriate. I do need to acknowledge a potential conflict of interest, however, in that I am a member of the DHHS Guidelines Panel. These most recent data from D:A:D and FHDH suggest this warning may need to be extended to other ARVs. Stay tuned.