CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts


1 University Hospital Basel, Basel, Switzerland, 2 University of Liverpool, Liverpool, UK, 3 Swiss Tropical and Public Health Institute, Basel, Switzerland Background: Aging of the HIV population complicates patient care due to a higher prevalence of comorbidities and related use of comedications leading to an elevated risk for drug-drug interactions (DDIs). However, our understanding how age impacts the magnitude and subsequently the management of DDIs in elderly is limited. This study aimed to simulate the DDI magnitude between boosted darunavir (DRV/r) and rivaroxaban in young and elderly subjects using a physiologically based pharmacokinetic (PBPK) model. Rivaroxaban is a narrow therapeutic index drug characterized by a complex metabolism; thus, its DDI with boosted HIV regimens has not yet been fully elucidated. Methods: A whole-body PBPK model was built in Matlab® including age- dependent physiological changes for the simulation of elderly subjects. The DRV/r drug model was successfully verified against observed clinical data in young volunteers. The predictive performance of our rivaroxaban model was checked against observed clinical data in a) young, b) elderly and c) young individuals treated with ritonavir (600 mg BID at steady state) and rivaroxaban. The verified drug models were used to assess the effect of age on the DDI magnitude between DRV/r (800/100 mg QD at steady state) and rivaroxaban (10 mg single dose) in 100 virtual subjects considering 5 age groups: a) 20-49, b) 50-64, c) 65-74, d) 75-84 and e) 85-94 years. Results: The developed PBPK model predicted the pharmacokinetics of rivaroxaban in young and elderly correctly. Predicted versus observed mean rivaroxaban AUC were 1148 and 1000 ng*h/mL for young and 1491 and 1839 ng*h/mL for elderly volunteers. The simulated versus observed rivaroxaban AUC in the presence of ritonavir was 2655 ng*h/mL and 2529 ng*h/mL with a resulting AUC ratio (rivaroxaban with / without ritonavir) of 2.31 and 2.53, respectively. Age did not impact the DDI magnitude between rivaroxaban and DRV/r (Tab. 1), because all drugs are similarly affected by age-dependent physiological changes. Of interest, virtual individuals aged 50-64 years commonly defined as “elderly” in HIV medicine, showed only a 12% increase in the AUC compared to younger subjects suggesting that this age cut-off is too low for pharmacological studies. Conclusion: PBPK modelling is a useful tool to overcome limited clinical data. Our predictions showed an age-dependent increase in the AUC of rivaroxaban in the absence and presence of DRV/r, but no changes in the DDI magnitude with age suggesting a similar management of this DDI in the elderly.

Perrine Courlet 1 , Catia Marzolini 2 , Matthias Cavassini 1 , Manuel Battegay 2 , Susana Alves Saldanha 1 , Deolinda Alves 1 , Vreneli Waelti Da Costa 1 , Chantal Csajka 1 , Laurent A. Decosterd 1 1 Lausanne University Hospital, Lausanne, Switzerland, 2 University of Basel, Basel, Switzerland Background: Antiretroviral therapy has transformed HIV infection from a deadly disease into a chronic condition. HIV-infected individuals live longer, experience age-related physiological changes and comorbidities and are thus predisposed to the risk of polypharmacy, drug-drug interactions (DDIs) and inappropriate medication use which may harm this vulnerable population. This study compared the prevalence of these issues in young and elderly person living with HIV (PLWH). Methods: Individuals enrolled in 2 centres from the Swiss HIV Cohort Study were contacted before their bi-annual follow-up visit to fill in a formwith all their current medications. Drugs were grouped according to the ATC classification. The medications use, polypharmacy (defined as being on > 5 non-HIV drugs) and potential DDIs (PDDIs) were compared in patients < 65 and ≥ 65 years old (elderly). Inappropriate medications included anticholinergic drugs (anticholinergic risk scale > 3) and benzodiazepines, as these drugs have been associated to an increased risk of falls, impaired cognition, loss of independence and hospitalization in the elderly. PDDIs for the most prescribed therapeutic classes (i.e. cardiovascular and central nervous system (CNS) drugs) were screened using the Liverpool drug interaction database. Results: A total of 906 PLWH were included: 794 were < 65 (median 49, IQR 40-55) and 112 ≥ 65 (71, 67-73) years old. 47% of PLWH received an integrase inhibitor based regimen and this proportion did not differ between the 2 groups. Elderly had a higher number of comedications (median 4, IQR 2–6) than younger PLWH (1, 0–3). Polypharmacy was more frequent in elderly compared to the younger group: 44% vs 12%. Type of medications and PDDIs differed according to the age group: cardiovascular drugs use and PDDIs (amber, red) with this drug class were more common in elderly (21% of overall prescribed drugs; 14% of cardiovascular drugs involved in PDDIs) whilst CNS drugs were more prescribed and mainly involved in PDDIs in younger PLWH (12%; 12%) (figure 1). Inappropriate medications were found in 13% of elderly, mostly benzodiazepines. Conclusion: PDDIs remain common in the era of integrase inhibitors and inappropriate prescribing practices constitute an additional burden in elderly. Research efforts must be pursued to improve the care of PLWH, particularly elderly. Clinicians should maintain a proactive approach for the recognition and management of DDIs or prescribing issues traditionally encountered in geriatric medicine.

Poster Abstracts

468 THE ROLE OF OATP1B1 IN GRAZOPREVIR DRUG-DRUG INTERACTIONS AND THE ELDERLY Hannah Kinvig 1 , Felix Stader 2 , Owain Roberts 1 , Andrew Owen 1 , Catia Marzolini 2 , Marco Siccardi 1 1 University of Liverpool, Liverpool, UK, 2 University Hospital Basel, Basel, Switzerland Background: Grazoprevir (GZR) is a hepatitis C (HCV) NS3/4A protease inhibitor which can be combined with antiretroviral drugs to treat HIV/HCV co-infected patients. Coadministration with boosted darunavir (DRV/RTV) is contraindicated as it increases GZR AUC and Cmax 7.5-fold and 5.3-fold. Although assumed to be caused by OATP1B1 and CYP3A4 inhibition, the mechanism of this drug-drug interaction (DDI) has not been fully elucidated. GZR also exhibits a 20% increase in AUC in elderly patients and the role of OATP1B1 remains unclear. The current study quantified OATP1B1-mediated transport of GZR in the presence of DRV and RTV in vitro and evaluated the expression of OATP1B1 in primary hepatocytes from both young and elderly donors. Methods: Pooled human cryopreserved hepatocytes were suspended in Krebs-Henseleit buffer in 24-well cell culture plates and incubated with GZR (0.1µM) and either DRV or RTV (0.01-33µM) for 2 minutes at 37°C. Transporter uptake was terminated using ice cold phosphate buffered saline (PBS) followed

467 DRUG INTERACTION MAGNITUDES IN YOUNG VS ELDERLY: EXAMPLE OF RIVAROXABAN–DARUNAVIR/R Felix Stader 1 , Marco Siccardi 2 , Hannah Kinvig 2 , Manuel Battegay 1 , Melissa A. Penny 3 , Catia Marzolini 1

CROI 2019 172

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