1 St Stephen's Centre, Chelsea & Westminster Foundation Trust, London, UK ... Centre, Royal Liverpool & Broadgreen University Hospital, Liverpool, UK.
PS6/1
Tenofovir (TFV) pharmacokinetics (PK) in HIV infected individuals over 40 years of age M Cevik1, L Dickinson2, 3, A Ahmed1, R Jones1, D Back3, B Ward1, D Asboe1, A Pozniak1, M Boffito1 St Stephen’s Centre, Chelsea & Westminster Foundation Trust, London, UK NHIR Biomedical Research Centre, Royal Liverpool & Broadgreen University Hospital, Liverpool, UK 3 Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK 1
2
Background 1 • With effective HAART survival in HIV-infected people has increased • HIV positive population is ageing • 25% of patients are now aged over 50 • 50% will be over 50 in 2015
Xxx et al. xxx 20xx; Gebo et al BMJ 2009
In the era of HAART Relative risk of death among patients with HIV 0.6
0.57
RR of death (95% CI)
0.45
0.3
0.21 0.16
0.15
0.14 0.09
0
(95% CI)
1996-1997
1998-1999
(0.51 - 0.64)
(0.18 - 0.24)
2000-2001
2002-2003
(0.13 - 0.18)
(0.11 - 0.16)
2004-2005
(0.07 - 0.12)
% of patients expected to survive
5yrs
10yrs
15 yrs
Age < 45
99%
96%
91%
Age > 45
95%
87%
72% Porter et al IAS 2007 TuPeB093
Background 2 • Ageing with HIV raises concerns about long-term use of HAART and management strategy • Uncertainty of antiretroviral drug efficacy or toxicity owing to changes in drug disposition with increasing age is a current therapeutic dilemma • The deterioration of renal function is multifactoral and increasing age and HAART may contribute Fisher et al Retrovirology 2010; Goicoechea et al JID 2008
Background 3 • Tenofovir Disoproxil Fumarate (TDF) is an oral pro-drug of TFV • TFV undergoes renal clearance by glomerular filtration and active tubular secretion • Its secretion is an active process that depends on efflux by transporters as multidrug resistance protein (MRP) 2 and MRP 4 • TFV is relatively safe, however renal dysfunction following exposure has been reported Kearney et al Clin Pharmacokinet 2004; Ray et al JID 2008
Therapeutic drug monitoring (TDM) in elderly • Data on antiretroviral concentrations in older patients are scarce • Lopinavir, atazanavir and darunavir showed to achieve higher exposure in older individuals • In our small cohort at C+W: ❖ Plasma concentrations of efavirenz were similar to younger patients ❖ Predicted clearance of darunavir/r OD was lower and drug exposure higher in patients over 50 Avihingsanon et al Glasgow 2008; Crawford et al AIDS Res Hum Retroviruses 2010; Dickinson et al 12th IWCPHT 2011; Ahmed et al EACS 2011
Objectives • To investigate plasma concentrations of TFV* in HIV positive patients over 40 • To use these findings to guide the management of older individuals on TDF • *TDM of TFV is NOT performed routinely in clinical practice • We introduced it as a service evaluation in HIV-infected individuals over 50 years of age in our dedicated clinic at C+W • We also collected data in 3 individuals between 40 and 50 years of age
Population Jan 2010 – April 2011
C+W general clinics
C+W OVER 50 clinic
54 patients (2 female) Median age 56 years (40-81)
12 PI/r - based
33 NNRTIbased
9 other
Methods • Since trough concentrations are difficult to collect in routine settings, samples were drawn randomly and population pharmacokinetics applied (NONMEM, v. VI 2.0) using previously published models1 to predict: apparent oral clearance (CL/F) area under the curve (AUC0-24) trough concentration (C24) • Linear regression analysis was used to assess the relationship between age and exposure to TFV • PK parameters of patients of patients < 60 versus > 60 years of age were compared using the Mann-Whitney U test (p
