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The 20th International Workshop on
Clinical Pharmacology of Antiviral Therapy
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Courtney V. Fletcher, Pharm.D.
Professor and Director, Antiviral Pharmacology Laboratory
UNMC Center for Drug Discovery
University of Nebraska Medical Center
The 20th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy was held in Noordwijk, The Netherlands from May 14-16, 2019. In this report, I will highlight abstracts focused primarily on clinical pharmacologic issues related to the therapy of HIV infection that are of broad interest or might benefit from some expert clarification. This report does not cover all plenaries and data presented at the Workshop. For more information and to view presentations from the meeting please visit:
http://www.infectiousdiseasesonline.com/event/workshop/20th-international-workshop-clinical-pharmacology-hiv-hepatitis-antiviral-drugs
20th International Workshop on Clinical Pharmacology of HIV Hepatitis & Other Antiviral Drugs
May 14-16, 2019. Noordwijk, the Netherlands
The Clinical Pharmacology of Therapy for HIV Infection.
A. Drug Development
Development of HIV maturation inhibitors - progress, but challenges. Continued discovery and development of new HIV drugs remains important. Bevirimat (BVM) was the first maturation inhibitor to demonstrate clinical anti-HIV activity, but its development was discontinued due to a lack of efficacy against naturally occurring polymorphisms in the HIV gag region and decreased potency in the presence of human serum. GSK has two (known) HIV maturation inhibitors in clinical development, GSK2838232 and GSK3640254. The results of a phase II study of GSK2838232 were presented at CROI 2019 (abstract 142). 33 HIV-infected persons received one of 4 doses of GSK2838232 (20mg, 50mg, 100mg and 200mg) given with cobicistat for 10 days. The maximum reduction in plasma HIV RNA was seen with the 200 mg dose (1.7 log10). 2 subjects had treatment-emergent isolates associated with in vitro GSK2838232 resistance, one receiving 50 mg and one 100 mg. There were no serious adverse events. These data do provide evidence for continued development of GSK2838232, but the treatment emergent isolates in particular and need for cobicistat do point to some challenges.
Abstract 4 at this meeting presented data from a phase I study of GSK3640254. GSK3640254 is referred to as a 2nd or next generation maturation inhibitor because it shows similar antiviral activity against wild-type HIV-1 or HIV-1 with Gag polymorphisms. Healthy volunteers were enrolled in single, or multiple ascending dose studies with doses that ranged from 50-320 mg once daily for 14 days. The PK profile of GSK3640254 was characterized by slow absorption with a Tmax of 4 hours, and a half-life of ≈ 24 hours (note, without a PK booster). There were no serious adverse events. These PK data support moving GSK3640254 forward to a proof of concept study in HIV-infected persons.
A Phase IIa Study of a Novel Maturation Inhibitor GSK2838232 in HIV patients - (03/15/19)
The Initial Phase I Evaluation of the Safety, Tolerability, and Pharmacokinetics of GSK3640254, a Next-Generation HIV Maturation Inhibitor, as Assessed in Healthy Subjects - (05/20/19)
Phase 1 results show safety and once-daily potential of new HIV maturation inhibitor - Mark Mascolini - (05/16/19)
NCT03784079 (https://clinicaltrials.gov/ct2/show/NCT03784079?term=GSK3640254&rank=2 ) is a proof of concept study of GSK3640254 in HIV-infected persons. According to the clinicaltrials.gov website, last updated on June 20, 2019, this study is presently suspended, for what is stated on the website as: "pending additional virology analysis because some participants receiving GSK3640254 developed treatment emergent MI RAMs on Day 11". Stay tuned.
Oral and Long-Acting Cabotegravir: predicting drug-drug interactions and PK in special populations. Following the results of the ATLAS and FLAIR studies of long acting cabotegravir (LA-CAB) and rilpivirine (LA-RPV) these drugs have reached late stage development. That said, there will be an ongoing need to understand potential drug-drug interactions as well as dosing in special populations such as persons with renal or hepatic dysfunction. Such studies are challenging, if not unrealistic, to be performed with the long-acting formulation, and thus will have to be conducted with the oral drug and extrapolated to the long-acting. As an example of this approach, rifampin is a potent inducer of UGT1A1 and has been shown to decrease CAB concentrations (following oral CAB administration) by > 50% and co-administration will be contraindicated (see https://aac.asm.org/content/61/10/e00487-17 ). Physiologically-based PK (PBPK) modeling studies have subsequently been performed for both LA-CAB and LA-RPV that have predicted an almost 50% decline in CAB concentrations and an 80% decline in RPV concentrations with rifampin coadministration (https://academic.oup.com/jid/article-abstract/219/11/1735/5253242 ). The modeling study confirmed the findings of the oral study and provides the basis for contraindication of LA-CAB and LA-RPV coadministration with rifampin.
Abstract 18 evaluated the potential for enzyme induction and inhibition of UGT1A1 to affect CAB concentrations, using a PBPK model developed for oral CAB. As above, CAB is primarily metabolized by the UGT1A1 hepatic enzyme. Interactions with a weak UGT inducer, phenobarbital, and potent UGT inhibitors, atazanavir (of UGT1A1) and mefenamic acid (of UGT1A9, a minor pathway for CAB) were evaluated. Model predictions found little effect on CAB concentrations from the UGT inhibitors atazanavir and mefenamic acid and that coadministration with LA-CAB would be acceptable. The weak inducer phenobarbital was predicted to decrease CAB concentrations by 28%, which would likely be clinically acceptable. This work illustrates the need for modest-to-potent inducers to be evaluated on a drug-by-drug basis, as the potential exists for a clinically significant reduction in CAB concentrations.
Utilization of physiologically based pharmacokinetic modelling (PBPK) to predict the effect of UGT enzyme inhibition and induction on the systemic exposure of Cabotegravir - (05/26/19)
While not presented at this meeting, there are 2 recent publications that I think are relevant to this commentary concerning PK in special populations. One that evaluated the effect of renal insufficiency on CAB concentrations and the other the effect of hepatic dysfunction on CAB concentrations. In the case of renal insufficiency, CAB concentrations after oral administration were evaluated in 8 healthy volunteers without renal insufficiency and in 8 persons with severe renal insufficiency (creatinine clearance < 30 mls/min) (https://www.ncbi.nlm.nih.gov/pubmed/30809978 ) . There was no difference in CAB AUC and Cmax values between the persons without and those with severe renal insufficiency: geometric least squares ratios for AUC and Cmax were 0.97 and 1.01, respectively. These data indicate the oral CAB can be administered to persons with renal insufficiency without dose adjustment; this recommendation should extrapolate to LA-CAB as well. A similar study was done in persons with moderate hepatic impairment (Child-Pugh score, 7-9) (https://www.ncbi.nlm.nih.gov/pubmed/30811880 ). CAB PK were determined after a single oral dose of 30 mg. When compared to healthy volunteers, there was a modest, approximately 30%, reduction in CAB concentrations in the persons with hepatic impairment. Remember it is unbound drug that is able to cross biologic membranes and exert a pharmacologic effect, and that CAB is highly, >99%, bound to plasma proteins. Unbound CAB concentrations were measured and were found to be increased, by 40% at 2 hours post dose and 55% at 24 hours post dose (trough concentration). This increase in free drug concentrations is unlikely to be clinically significant, and oral CAB and by extrapolation LA-CAB is likely acceptable for administration to persons with mild to moderate hepatic insufficiency. These data do not, however, provide any recommendation for persons with severe hepatic insufficiency.
Accelerating development of pediatric formulations. The development of drugs and formulations, including pediatric-appropriate fixed dose combinations, lags considerably behind that in adults. Abstract 8 discussed the Global Accelerator for Pediatric Formulation (GAP-f) initiative to speed pediatric formulation development for HIV, TB and hepatitis C. This initiative represents a partnership that includes the WHO, the Clinton Health Access Initiative, pharmaceutical industry and the community. You can access the GAP-f home page here for more information: http://www.gap-f.org . There is a tremendous unmet need and any and all efforts are welcome.
B. HIV Pharmacotherapy
Assessment of recent (short-term) and long-term medication adherence. The role of adherence in achieving high rates of HIV prevention with PrEP and high rates of virologic suppression with ART is indisputable. Quantitation of tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) has emerged as an adherence measure of highly predictive PrEP and ART success (see, for example,: https://www.ncbi.nlm.nih.gov/pubmed/30942881 ; https://www.ncbi.nlm.nih.gov/pubmed/30137238 ; https://www.ncbi.nlm.nih.gov/pubmed/25065857 ). The TFV-DP half-life in DBS is ≈ 17 days, thus reflecting dosing over the last 8+ weeks. A limitation then of the TFV-DP in DBS method is detection of recent non-adherence. Abstract 14 explored this issue in a comparison of TFV and FTC measurements in plasma, PBMCs, upper layer packed cells (ULPC), DBS and a whole blood microsampler (Mitra). As expected, TFV-DP in DBS could not discriminate recent dose changes. The investigators found that TFV-DP and FTC-TP in PBMCs (half-lives of ≈ 100 hours and 35 hours, respectively) were best able to discriminate recent changed in dosing patterns.
An exploration of adherence measures to detect recent changes in Truvada® dosing patterns - (05/20/19)
The half-life of FTC-TP in PBMCs and DBS is essentially the same, ≈ 35 hours and reflects recent dosing (2 to 7 days). This is in contrast to the considerable difference in the half-lives of TFV-DP between PBMCs and DBS of ≈100 hours vs 17 days. A just published study evaluated FTC-TP and TFV-DP in DBS as measures of short- and long-term adherence to PrEP (see: https://www.ncbi.nlm.nih.gov/pubmed/31095005 ). FTC-TP, as an indicator of poor short term non-adherence was the strongest factor predicting future nonretention in the study. While quantification of FTC-TP and TFV-DP in DBS is analytically complex, this approach could improve on our knowledge of patient adherence, both short and long-term, and thereby improve retention in care and therapeutic outcomes.
Abstract 13 evaluated TFV-DP in PBMCs following administration of different TAF/FTC dosing regimens (33%, 67% and 100% of daily dosing) to 44 healthy volunteers. There were two important findings from this study. First, across the 3 different dosing regimens, TFV-DP concentrations with TAF remained equivalently higher than those with TDF, indicating the dosing regimen did not affect the improved intracellular drug delivery with TAF. Second, the TFV-DP concentrations were approximately proportional across the 3 dosing regimens indicating an ability to discriminate different dosing patterns. Given TAF/FTC is under FDA review for approval for PrEP following the results of the DISCOVER trial presented at CROI 2019 (abstract 104; http://www.croiwebcasts.org/p/2019croi/104 ) this information will be useful to adopt measurement of TFV-DP with TAF administration as a measure of adherence.
Cobicistat boosted regimens should not be used in pregnant women. Abstract 10 evaluated atazanavir (ATV) pharmacokinetics when given with cobicistat in six pregnant women. PK assessments were performed during the 2nd and 3rd trimesters and 6-12 weeks postpartum. Data are only available for 3 women in 2nd trimester and for 5 women at 3rd trimester and postpartum. Median ATV trough concentrations were: 2nd trimester, 160 ng/mL; 3rd trimester, 120 ng/mL; and postpartum, 450 ng/mL. These trough values are 20%, 15% and 56%, respectively, of those in nonpregnant individuals taking ATV/cobi 300/150 mg once daily. All 6 women had plasma HIV RNA < 50 copies/mL at delivery.
These ATV levels are low. They approximate the trough concentrations seen with the unboosted dose of 400 mg once daily and the often quoted threshold concentration for ATV of 150 ng/mL. As such, they are on the borderline of efficacy. They are also in sharp contrast to those found when ATV is given with ritonavir (RTV) in pregnant women. In a study of 103 pregnant women in sub-Saharan Africa who received ATV/RTV, 300/100 mg once daily, median ATV concentrations were: 2nd trimester, 631 ng/mL; 3rd trimester, 665 ng/mL and postpartum, 914 ng/mL (see: https://www.intmedpress.com/journals/avt/abstract.cfm?id=2936&pid=48 ).
Differences in cobi vs. RTV boosting in pregnancy have also been observed for darunavir and elvitegravir, with trough concentrations approximately 90% lower in the 3rd trimester than postpartum. Thus, in pregnant women there are profound differences between the PK boosters cobicistat and ritonavir. Collectively, these PK data led the FDA to require changes to drug labels for atazanavir, darunavir and elvitegravir that therapy with atazanavir, darunavir or elvitegravir plus cobicistat as a PK booster should not be continued or initiated during pregnancy (see: https://www.ncbi.nlm.nih.gov/pubmed/30946163 ).
PHARMACOKINETICS OF ATAZANAVIR BOOSTED WITH COBICISTAT DURING PREGNANCY AND POSTPARTUM - (05/20/19)
Ritonavir concentrations increase in older persons. There is an age-related decline in renal function that leads to increased concentrations of renally-eliminated drugs, and a basis to expect a similar age-related decline in hepatic function and an increase in concentrations of hepatically-metabolized drugs. Data supporting the latter, however, are sparse. Abstract 15 evaluated the effect of aging on ritonavir (RTV) concentrations in a novel and elegant manner. They used physiologically-based PK modeling (PBPK) of ritonavir, in which they were able to simulate age related changes in organ weight and blood flow in a virtual population of persons 20-99 years of age. Then, they compared these predictions with measured RTV concentrations in younger (20-50 years) and older (> 55 years) persons. The predicted and measured RTV concentrations were in close agreement, providing validation of the PBPK modeling approach. RTV predicted and measured AUCs were 5,246 vs 5,296 ng*h/mL in younger and 6,568 vs 6,609 ng*h/mL in older persons, respectively. The PBPK modeling data found the RTV PK difference arises from an age-related decrease in hepatic metabolism.
These results show an average 25% increase in RTV concentrations in older compared with younger persons. While modest, I would not dismiss the potential of any clinical significance. I'd call readers attention to abstract 518 at CROI 2019 showing sex-based outcome differences in persons receiving 3rd line ART. In this study (ACTG 5288) more women stayed on a RTV-boosted regimen (LPV or ATV). Women had higher rates of Grade 3 signs and symptoms, serious adverse events and hospitalizations. RTV concentrations have been shown (in other studies) to be approximately 30% higher in women. The authors of the CROI abstract raise the question of whether women had more adverse events than men because of higher RTV concentrations than men? If this were true, then the 25% higher RTV concentrations in older persons could lead to higher rates of RTV-associated adverse reactions in older persons. I believe clinicians caring for older persons who are on RTV, and really all medications, to inquire about tolerance, listen carefully to what the patient is telling you, and consider the possibility of age-related changes in PK contributing to higher rates of adverse drug reactions.
Physiologically based pharmacokinetic modelling to determine pharmacokinetic alterations driving ritonavir exposure changes in aging people living with HIV - (05/16/19)
Model suggests physiologic changes with aging underlie ritonavir PK shifts - Mark Mascolini (05/20/19)
https://www.croiconference.org/sessions/important-sex-differences-outcomes-individuals-presenting-third-line-art
C. Drug-Drug Interactions
No detrimental interaction with high-dose rifapentine (RPT) and efavirenz-containing ART. A major obstacle to the control of TB is poor adherence to lengthy and complicated treatment regimens. Thus, there is a high priority to develop more potent, shorter course regimens. A previous study from the TB Treatment Consortium (TBTC 29) for treatment of TB found that higher rifapentine (RPT) exposures were associated with higher rates of sputum sterilization at two months. ACTG 5349/TBTC 31 is a study comparing two short-course TB treatment regimens, each using high-dose RPT, 1200 mg once daily. Rifamycins are known, potent inducers of CYP metabolism and the potential exists for an adverse interaction with efavirenz (EFV). No clinically-significant interaction was found between usual dose RPT (approximately 10 mg/kg once daily) given with isoniazid for prevention of TB in HIV-infected persons; however, it is unknown whether high-dose RPT would have a more potent enzyme-inducing effect and lower EFV concentrations. Abstract #1 presented by Podany and colleagues showed this was not the case. The proportion of participants with EFV plasma concentrations > 1 mg/L (a commonly accepted threshold concentration for EFV) did not differ between the post TB treatment/no RPT phase (90%) compared with the weeks 4 and 8 TB treatment/on RPT phases (89% and 93%, respectively). The data from this study provide pharmacokinetic and pharmacodynamic support for coadministration of EFV-containing ART with a high-dose RPT-containing TB treatment regimen.
A website for clinical cases on drug-drug interactions in people living with HIV. In the routine care of persons with HIV, clinicians gain experience about managing drug-drug interactions. Most of the knowledge is learned on a case-by-case basis and understandably goes unreported in the medical literature. That "loss" of knowledge is unfortunate. At this meeting, a group of European clinical pharmacologists announced their new initiative and website to create an open-access web page and registry for clinical cases on drug interactions.
This is fantastic idea, and I strongly encourage clinical pharmacologists and clinicians to support this project.
You can access the website here: www.clinicalcasesDDIs.com
For more information, you can send an email to: info(at)clinicalcasesddis.com
Abbreviations
%CV, percent coefficient of variation
3TC, lamivudine
ABC, abacavir
ACTG, AIDS Clinical Trials Group
ARV, antiretroviral drug
ART, combination antiretroviral therapy
AUC, area under the concentration-time curve
ATV, atazanavir
CAB, cabotegravir
CAB-LA, long-acting cabotegravir
Cmax, maximum drug concentration
COBI, cobicistat
ConMed, concomitant medication
CrCL, creatinine clearance
CYP, cytochrome P450 drug metabolizing enzymes
DDI, drug-drug interaction
DHHS, Department of Health and Human Services
DTG, dolutegravir
DRV, darunavir
eGFR, estimated glomerular filtration rate
EFV, efavirenz
ESRD, end-stage renal disease
EVG, elvitegravir
FDA, Food and Drug Administration
FTC, emtricitabine
GALT, gut-associated lymphatic tissue
HCV, Hepatitis C virus
HD, hemodialysis
IM, intramuscular
INSTI, integrase strand transfer inhibitor
OATP, organic anion transporting polypeptide (uptake transporters)
PA-IC90, protein-binding adjusted 90% inhibitory concentration
PBMCs, peripheral blood mononuclear cells
PD, pharmacodynamics
P-gp, p-glycoprotein (efflux transporter)
PK, pharmacokinetic
PI, protease inhibitor
RAL, raltegravir
RIF, rifampin
RTV or r, ritonavir
RBV, ribavirin
RPV, rilpivirine
RPV-LA, long-acting rilpivirine
TAF, tenofovir alafenamide
TDF, tenofovir disoproxil fumarate
TFV, tenofovir
TFV-DP, tenofovir diphosphate
Trough, concentration immediately before the next dose
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