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12th International Workshop on
Clinical Pharmacology of HIV Therapy Report by Courtney Fletcher, PharmD
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Courtney V. Fletcher, Pharm.D.
Dean and Professor
College of Pharmacy
University of Nebraska Medical Center
986000 Nebraska Medical Center
Omaha, NE 68198
The 12th International Workshop on Clinical Pharmacology of HIV Therapy was held in Miami, Florida from April 13-15, 2011. This meeting continues to be a premier meeting focused on clinical pharmacologic issues in the treatment of HIV infection. Furthermore, it remains a venue for scientific interactions among scientists in academic, pharmaceutical industry and regulatory authorities, which is an almost unique attribute. In this report I will highlight abstracts focused on pharmacologic issues I think are of broad interest or might benefit from some expert clarification. I will discuss abstracts in five broad categories: dose optimization, new drugs, drug interactions, special populations, and compartments.
TOPICS
- FEM-PrEP Study & intracellular triphosphate concentrations of ZDV and 3TC according to HIV infection status and gender
- RAL once daily study (QDMRK)
- ATV concentrations in 12 healthy volunteers when given with either 100 mg or 50 mg of RTV for 10 days
- 3TC dose of 150 mg once daily, compared with the usual 300 mg once daily dose
- BMS-663068 is an investigational HIV attachment inhibitor - PK
- Dolutegravir GSK Integrase - PK studies
- Elvitegravir and cobicistat & H2 receptor antagonist such as famotidine, proton pump inhibitors - PK studies
- PK and PD effects of the QUAD tablet (EVG, COBI, FTC and TDF) on the oral contraceptive, Ortho Tri-Cyclen Lo were evaluated
- dose of ATV (given with RTV) in the 2nd trimester as well as the 3rd trimester of pregnancy
Abbreviations
%CV, percent coefficient of variation
ABC, abacavir
ACTG, adult AIDS clinical trials group
APV, amprenavir
ARV, antiretroviral drug
ART, antiretroviral drug therapy
AUC, area under the concentration-time curve
ATV, atazanavir
BOC, boceprevir
Cmin, minimum drug concentration
CNS, central nervous system
COBI, cobicistat
CSF, cerebrospinal fluid
Ctrough, concentration immediately before the next dose
CYP, cytochrome P450 drug metabolizing enzymes
DRV, darunavir
ddI, didanosine
EFV, efavirenz
EVG, elvitegravir
FTC, emtricitabine
ETR, etravirine
fAPV, fosamprenavir
IC50, concentration of drug required to inhibit viral replication in vitro by 50%
IDV, indinavir
IM, intramuscular
IQ, inhibitory quotient
3TC, lamivudine
LPV, lopinavir
MVC, maraviroc
NVP, nevirapine
NRTI, nucleoside reverse transcriptase inhibitor
NNRTI, non-nucleoside reverse transcriptase inhibitor
PACTG, pediatric AIDS clinical trials group
PBMCs, peripheral blood mononuclear cells
PD, pharmacodynamic
PG, pharmacogenetics/pharmacogenomics
PK, pharmacokinetic
PI, inhibitor of HIV protease
PrEP, pre-exposure prophylaxis
r or RTV, ritonavir
RAL, raltegravir
RBT, rifabutin
RBV, ribavirin
SQV, saquinavir
SC, subcutaneous
TDF, tenofovir disoproxil fumarate
TFV, tenofovir
TVR, telaprevir
TDM, therapeutic drug monitoring
TPV, tipranavir
ZDV, zidovudine
I. Dose Optimization
The issue of dose optimization is important for several reasons, ranging from finding the right dose for an individual patient that achieves the highest probability of therapeutic success with the lowest risk of adverse events, to as a strategy to decrease the cost of antiretroviral therapy in order to increase the delivery of therapy to more individuals. A plenary/round table discussion on Dose Optimization and Simplification focused on the decrease cost to increase access issue. Here are some compelling reasons to pursue this research: "over 90% of HIV-infected individual live in very poor countries where the cost of antiretroviral treatment can still be a major barrier to access" (Andrew Hill, Liverpool University); "antiretrovirals consume 50% of the drug budget for South Africa...the need to reduce antiretroviral prices is becoming more pressing as ART scale up continues in low- and middle-income countries" (Gary Maartens, University of Cape Town); and "while 5 million individual are currently accessing ARV for treatment, 10 million more require therapy" (Steve Becker, Bill & Melinda Gates Foundation).
Abstract P-31 is a good example of one dose optimization strategy. This study investigated ATV concentrations in 12 healthy volunteers when given with either 100 mg or 50 mg of RTV for 10 days. The AUC of ATV when given with 50 mg of RTV was 47.09 mg*h/L and was 50.62 mg*h/L with 100 mg of RTV; the 90% CI of the ratio was 82.5 to 116.38. The ATV trough concentrations were 0.59 mg/L with 50 mg of RTV and 0.79 mg/L with 100 mg; all trough concentrations were above 0.15 mg/L, which is the suggested threshold concentration. There was also no difference in ATV Cmax with the 2 RTV doses. In the 10 day treatment periods, total and LDL cholesterol significantly increased with the 100 mg RTV dose, whereas there were no significant changes with the 50 mg RTV dose. These data in healthy volunteers indicate ATV exposure was equivalent when given with either 100 mg or 50 mg of RTV, but there were fewer adverse effects on lipid metabolism with the 50 mg RTV dose. These data provide a basis for further studies in HIV-infected persons as a strategy to minimize RTV-associated adverse effects, and as a strategy to decrease the costs of therapy.
While the ATV/RTV example above provides an example of a dose optimization lead worth pursuing, two other abstracts are examples of strategies that do not. The first, abstract O-05 evaluated whether a 3TC dose of 150 mg once daily, compared with the usual 300 mg once daily dose, achieved bioequivalent intracellular concentrations of the active metabolite, 3TC-triphosphate. 24 healthy volunteers participated in this study. The geometric mean 24-hour AUC of 3TC-triphosphate from the 300 mg dose was 59.5 pmol/10^6 cells; this value for 150 mg was 44.0 pmol/10^6 cells. The geometric mean 24-hour concentrations were 1.49 pmol/10^6 cells and 1.23 pmol/10^6 cells for the 300 mg and 150 mg 3TC doses, respectively. The geometric mean ratios for AUC and trough concentration were 0.73 and 0.82, respectively, indicating that the 150 mg dose was not bioequivalent to the 300 mg dose. This was a reasonable study to perform. It was possible the intracellular formation of 3TC-triphosphate might be saturable, and thus lower doses would achieve intracellular concentrations the same as higher doses. This study showed, however, this was not the case. Because bioequivalence was not demonstrated, I don't see a pharmacologic basis to pursue a lower 3TC dose as a dose optimization strategy.
I discussed the results of the RAL once daily study (QDMRK) in my CROI 2011 report. This trial of once vs. twice daily RAL in 770 treatment-naive persons demonstrated once daily therapy was inferior to twice daily, with overall proportions of subjects with HIV-RNA <50cpm at week 48 of 83.2% vs. 88.9%, respectively. Some PK data were provided at CROI and demonstrated RAL trough concentrations with 800 mg once daily were substantially lower than 400 mg twice daily dose. At this meeting, additional PK data were provided in abstract O-09. Ctrough values, from the 24-hour intensive PK studies, were lower for once daily RAL: the geometric mean was 40nM for 800mg once daily versus 257nM for 400 mg twice daily. The trough concentration were similarly lower from the spare/population PK data: the geometric mean was 83nM for once daily and was 380nM for twice daily. Significant relationships were also found between RAL concentrations and virologic response. For example, the odds ratio for achieving HIV-RNA below 400 or 50 copies/mL increased with increasing concentrations, and the odds of virologic failure decreased with increasing RAL concentrations. From the presentation at the meeting, no clear breakpoint or threshold RAL concentrations could clearly be identified. From the data, it looks to me that a trough concentration less than approximately 60 nM certainly increases the risk of virologic failure. Two more comments, first, these data indicate RAL and the investigational integrase inhibitors elvitegravir and dolutegravir all exhibit pharmacodynamic relationships between trough concentrations and virologic response. Second, this RAL study is a clear example of a potential hazard for dose optimization efforts: for all antiretrovirals, there is some threshold concentration you can't go below without increasing the risk of virologic failure for a patient.
Clinical Pharmacology at CROI 2011 (HIV & HCV) - Courtney V. Fletcher, Pharm.D. Dean and Professor College of Pharmacy University of Nebraska Medical Center 986000 Nebraska Medical Center (03/14/11)
II. Drug Development
BMS-663068 is an investigational HIV attachment inhibitor. Following oral administration, BMS-663068 is converted to BMS-62659, which is the active drug that binds to the viral envelope and prevents attachment of HIV to the CD4 cell receptor. The PK were described in abstract O-04. The most important findings were that administration of an extended release (ER) formulation resulted in a lower Cmax and a higher Cmin than the immediate release (IR) formulation. This will be useful because nausea is the most common side effect (to date) and appears to be associated with a high Cmax. Thus, because the ER formulation reduces Cmax but maintains the Cmin, this formulation should be better tolerated than the IR. Additionally, this abstract described the interaction between BMS-663068 and RTV, and reported RTV only modestly increases concentrations. The relationships between concentrations and response were explored in HIV treatment-naive and experienced persons receiving different doses administered once or twice daily, with or without RTV (abstract O-08). This study found an extremely wide range of baseline susceptibility to BMS-663068 from 0.33 to >1860 ng/mL. The change in HIV-RNA was correlated with the ratio of steady-state plasma concentration to baseline susceptibility (an inhibitory quotient), but the strongest predictor on response was baseline susceptibility. This most likely indicates that in clinical use (if the drug were to be approved), baseline susceptibility will need to be determined prior to use in an individual patient. Based on a virologically susceptible population, BMS-663068 doses without coadministration with RTV should be sufficient to suppress HIV replication. Further studies of BMS-663068 are planned.
III. Drug Interactions
Dolutegravir administration with EFV and TPV/RTV appears to be acceptable, and can be given with or without food.
Abstract O-02 described the PK of dolutegravir (DTG) when given with TPV/RTV and EFV in healthy volunteers. TPV and EFV are hepatic enzyme inducers, and both were found to reduce DTG concentrations. The DTG AUC and Cmin decreased 59% and 76%, respectively when given with TPV/RTV. DTG AUC and Cmin decreased 57% and 75% when given with EFV. Despite these significant reductions, the authors recommended that DTG dose adjustments were not necessary in integrase-inhibitor naive persons. This recommendation comes from the SPRING-1 study, which randomized 205 HIV-infected treatment-naïve persons to DTG doses of 10, 25 or 50 mg once daily, or once daily EFV, all in combination with FTC/TDF or ABC/3TC. At 24 weeks, the proportions of participants who had HIV-RNA < 50 copies/mL were: 10 mg DTG, 51/53 (96%); 25 mg DTG, 46/51 (90%); 50 mg DTG, 47/51 (92%); and EFV, 39/50 (78%). [http://www.springerlink.com/content/v01k54v57501h942/]
These data indicate that across DTG doses of 10 to 50 mg once daily, there were equal proportions of persons who responded. Pharmacodynamically, this suggests all of these doses achieved concentrations on the plateau portion of a DTG concentration-response curve. So the basis the authors of abstract O-02 have to conclude that DTG dose adjustments if given with TPV or with EFV, are not necessary is despite the decrease, DTG concentrations remain above those seen with the 10 mg once daily dose in the SPRING study, which were associated with the same virologic response as the 50 mg once daily dose. A few caveats are warranted. It will be necessary to confirm the DTG concentrations seen in the TPV and EFV interaction studies are seen in HIV-infected persons, that co-administration is well tolerated and virologic response is indeed not compromised. But, the approach the DTG investigators have used to establish the PD profile of this drug is solid and informed, and a good model for others.
The effect of food on the PK of DTG was described in abstract P-12. 50 mg of DTG was given to healthy volunteers in a fasting state, or with a low, moderate or high fat meal. Coadministration with food increased DTG concentrations. The DTG AUC increased by 33%, 41% and 66% with low, moderate and high fat meals, respectively. These increases in concentrations are not believed to adversely effect of safety of DTG, and therefore DTG should be able to be taken with or without food.
Elvitegravir and cobicistat should be given simultaneously or separated by 12h from an H2 receptor antagonist such as famotidine; no dosing restrictions appear necessary with proton pump inhibitors.
The solubility of cobicistat (COBI) decreases with an increasing gastric pH, and the potential may therefore exist for administration with acid reducing agents to decrease COBI concentrations and therefore, its PK boosting effect. The effect of acid reducing agents on the PK of elvitegravir (EVG) and cobicistat (COBI) were described in abstract P-13. 40 mg of famotidine (an H2 receptor antagonist) was given simultaneously and separated by 12 hours from EVG/COBI. The proton pump inhibitor (PPI) omeprazole was given 2 hours before EVG/COBI and also when separated by 12 hours from EVG/COBI. 32 healthy volunteers completed these PK evaluations.
The PK of EVG/COBI were not affected when given either 2 hours after or separated by 12 hours from the proton pump inhibitor omeprazole. No dosing restrictions should be necessary if EVG/COBI are given with a proton pump inhibitor. However, if EVG/COBI and a H2 receptor antagonist are to be coadministered, based upon the available data, they should be given simultaneously, or separated by 12 hours.
The QUAD tablet affects oral contraceptive concentrations and a higher dose of the ethinyl estradiol component may be needed.
The PK and PD effects of the QUAD tablet (EVG, COBI, FTC and TDF) on the oral contraceptive, Ortho Tri-Cyclen Lo were evaluated in 12 healthy female volunteers (abstract O-17). Coadministration with the QUAD tablet was associated with a decrease ethinyl estradiol concentration: AUC decreased 25%, Cmax decreased 6%, and Cmin was decreased 43%. Norelgestromin (the active metabolite of norgestimate) concentrations were increased by approximately 2.25-fold. There was no apparent effect of norgestimate/ethinyl estradiol on the concentrations of EVG or COBI. To evaluate whether coadministration with QUAD affected the PD (or contraceptive effect) of norelgestromin/ethinyl estradiol, concentrations of progesterone luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured. There was no change from baseline in progesterone levels, and no difference in the decrease in FSH levels seen with norgestimate/ethinyl estradiol administration alone or with QUAD. A greater decrease in LH levels was seen with norgestimate/ethinyl estradiol administration with QUAD than with norgestimate/ethinyl estradiol administration only. These data suggest the administration of norgestimate/ethinyl estradiol with QUAD maintains the suppression of LH and FSH even though concentrations of ethinyl estradiol were reduced. The authors recommended, however, because ethinyl estradiol concentrations were reduced when given with the QUAD tablet, that an increased dose of ethinyl estradiol, to at least 30 μg (from the 25 μg contained in Ortho Tri-Cyclen Lo) should be given to help ensure contraceptive effectiveness. The effect of ATV/RTV on ethinyl estradiol concentrations with given with Ortho Tri-Cyclen Lo is very similar, with a decrease in AUC of 19%, Cmax of 16% and Cmin of 37%. An increase in the ethinyl estradiol dose to 35 μg when given with ATV/RTV is recommended in the current FDA approved ATV label (dated 2/4/2011). I agree that an increase in the ethinyl estradiol dose seems prudent if norgestimate/ethinyl estradiol and EVG/COBI/FTC/TDF are coadministered, but whether that increase should be to 30 μg or to 35 μg is a bit uncertain.
IV. Special Populations
An increased dose of ATV (given with RTV) may be necessary in the 2nd trimester as well as the 3rd trimester of pregnancy, whether given with TDF or not.
Mark Mirochnick presented the results of an ongoing study of an increased dose of ATV (+RTV) with or without TDF in pregnant women (abstract O-10). In this prospective, non-blinded study, ATV/RTV was given at the usual dose of 300/100 once daily during the 2nd trimester, 400/100 during the 3rd trimester, and 300/100 from delivery through 2 weeks postpartum. Two cohorts separated by whether receiving TDF or not were evaluated. The target PK thresholds were the 10th percentile for AUC in non-pregnant adults taking the standard ATV/RTV dose of 300/100 of 29.4 μg*h/mL; the target for the C24 (or trough concentration) was 0.15 μg/mL, which is the suggested minimum trough concentrations. PK data for 58 women were presented.
Additional PK data were a median cord blood concentration of 0.15 μg/mL and a median ratio of cord blood to maternal plasma concentration at delivery of 0.14. These data indicate ATV exposure in the 2nd trimester is low regardless of whether TDF was coadministered. The increase in the ATV dose to 400/100 in the 3rd trimester compensated for the apparent increase in oral clearance of the drug and improved the proportions of women who met the AUC and C24 targets. The return to the usual ATV/RTV dose postpartum generally seemed to maintain exposure and the % achieving target goals as seen in the 3rd trimester. The present FDA-approved ATV label recommends an ATV/RTV dose of 400/100 for pregnant women during the 2nd or 3rd trimester who are also taking an H2 receptor antagonist (e.g. famotidine) or TDF. The data from this abstract suggest consideration should be given to using the increased dose of 400/100 in the 2nd and 3rd trimester for women who are not receiving TDF, because of the low ATV concentrations seen with the usual ATV/RTV dose.
V. Compartments
I am going to close with a few comments on the NRTIs and compartments. Pete Anderson presented work on the intracellular triphosphate concentrations of ZDV and 3TC according to HIV infection status and gender (abstract O-06). No difference was found in intracellular ZDV-triphosphate between individuals infected or not infected with HIV. However, 3TC-triphosphate concentrations were higher in those not infected with HIV. No difference in ZDV- or 3TC-triphosphate concentrations by gender was observed. However, the power to detect such a difference in this small sample size was low. These investigators have an ongoing study in approximately 100 HIV-infected subjects, which, hopefully, will provide a clear answer to this question, as other investigations have shown a difference in intracellular concentrations, and women have been shown to have a greater risk of certain NRTI adverse effects, such as lactic acidosis.
Two days after the conclusion of this HIV clinical pharmacology conference, the news was released that the FEM-PrEP trial has been stopped by the Data Safety Monitoring Board because of futility
[ http://www.FHI.org/en/AboutFHI/Media/Releases/FEMPrEP_statement041811.htm ].
FEM-PrEP was a randomized, placebo-controlled, clinical trial of the effectiveness of daily, oral FTC/TDF for HIV prevention among 1951 HIV-uninfected women in Kenya, South Africa and Tanzania. As of February 18, a total of 56 new HIV infections had occurred, with an equal number of infections in those participants who were randomized to FTC/TDF and those who received placebo. These results are disappointing, given the demonstrated efficacy of a TFV vaginal gel in preventing HIV infection in women (Caprisa 004) and the efficacy of oral FTC/TDF in preventing infection in men (iPrEx). But, are the results surprising? Sadly, we don't really know. In my opinion, there was a jump from PrEP concept to large phase III trials that left many fundamental clinical pharmacology questions unanswered. These include whether there are differences in NRTI phosphorylation (i.e. activation to the active moiety) between persons not infected with HIV compared with those infected (the population that constitutes the data on NRTI efficacy), whether there are differences in phosphorylation between men and women, and whether there are sufficient concentrations of the active triphosphate in the compartments necessary to prevent acquisition of HIV. Some of these questions are just now being addressed, such as in the work by Anderson at this meeting, and by Hendrix at CROI 2011, who found that TFV-diphosphate concentrations in vaginal tissue were 100 fold lower with oral TDF than with the vaginal TFV gel (abstract 35LB). I am pleased some of these fundamental clinical pharmacology questions are now being addressed; I sure wish they had done so much, much sooner.
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