ROC Curve
2- Hastane Ortamlar nda Yap lm Benzer Çal malar
Annexe 2 – 7: résumé de l’étude de la compétition portant sur les sites de liaison aux protéines plasmatiques entre le DTG et d’autres antirétrovirau fortement liés aux protéines plasmatiques. L’article traitant cette thématique doit encore être écrit.
Résumé:
The binding of substances to plasma proteins depends on two parameters, binding affinity (expressed as dissociation constant, Kd) and the number of binding sites (expressed as Bmax). Between subjects variability of these binding parameters has not yet been explored and could lead to a desynchronization between unbound and total concentrations. The purpose of the study was to investigate the binding of DTG when antiretrovirals highly bound to plasma protein-binding are added. The study was conduct using an equilibrium dialysis device. Antiretroviral to combine with DTG were selected according to two criteria: (i) the antiretroviral is currently used in therapeutic strategies in association with DTG and (ii) is expected to compete with DTG plasma protein binding sites. Four antiretrovirals were selected: rilpivirine, darunavir, atazanavir and etravirine. Regardless the antiretroviral added, DTG was systematically removed from its plasma protein binding sites (p<10-3). It can be concluded that association with these antiretrovirals may result in
170 Annexe 2 – 8: résumé de l’étude de la compétition portant sur les sites de liaison aux protéines plasmatiques entre le DRV et d’autres antirétrovirau fortement liés aux protéines plasmatiques. L’article traitant cette thématique doit encore être écrit.
Résumé:
The binding of substances to plasma proteins depends on two parameters, binding affinity (expressed as dissociation constant, Kd) and the number of binding sites (expressed as Bmax). Between subjects variability of these binding parameters has not yet been explored and could lead to a desynchronization between unbound and total concentrations. The purpose of the study was to investigate the binding of DRV when antiretrovirals highly bound to plasma protein-binding are added. The study was conduct using an equilibrium dialysis device. Antiretroviral to combine with DRV were selected according to two criteria: (i) the antiretroviral is currently used in therapeutic strategies in association with DRV and (ii) is expected to compete with DRV plasma protein binding sites. Three antiretrovirals were selected: etravirine, dolutegravir, raltegravir. Regardless the antiretroviral added, DRV was never removed from its plasma protein binding sites (p>0.05). It can be concluded that association with these antiretrovirals may not result in desynchronization between DRV unbound and total concentrations.
171 Annexe 2 – 9: résumé de l’étude de la compétition portant sur les sites de liaison aux protéines plasmatiques entre le ATV et d’autres antirétrovirau fortement liés aux protéines plasmatiques. L’article traitant cette thématique doit encore être écrit.
Résumé:
The binding of substances to plasma proteins depends on two parameters, binding affinity (expressed as dissociation constant, Kd) and the number of binding sites (expressed as Bmax). Between subjects variability of these binding parameters has not yet been explored and could lead to a desynchronization between unbound and total concentrations. The purpose of the study was to investigate the binding of ATV when antiretrovirals highly bound to plasma protein-binding are added. The study was conduct using an equilibrium dialysis device. Antiretroviral to combine with ATV were selected according to two criteria: (i) the antiretroviral is currently used in therapeutic strategies in association with ATV and (ii) is expected to compete with ATV plasma protein binding sites. Four antiretrovirals were selected: etravirine, dolutegravir, raltegravir. Regardless the antiretroviral added, ATV was never removed from its plasma protein binding sites (p>0.05). It can be concluded that association with these antiretrovirals may not result in desynchronization between ATV unbound and total concentrations.
172
4.
Quatrième partie : intérêts de la forme libre dans le suivi thérapeutique
pharmacologique des antirétroviraux chez des patients VIH
Annexe 2-10
Article accepté dans Journal of Antimicrobial Chemotherapy. Le travail portait
sur l’intérêt de l’étude de la forme libre pour l’atazanavir et le darunavir chez les patientes
VIH enceinte.
Journal of Antimicrobial Chemotherapy – Leading article
Antiretroviral unbound concentration during pregnancy: piece of interest in the puzzle?
Running title: Antiretroviral therapeutic drug monitoring during pregnancy Metsu D.1,2 ; Toutain P.L. 3 ; Chatelut E. 2,4 ; Delobel P.5,6 ; Gandia P*1,3.
Adresses :
1 Laboratoire de Pharmacocinétique et de Toxicologie, CHU Toulouse, France ; 2 CRCT, Université de Toulouse, Inserm, UPS, Toulouse, France; 3 Toxalim, Université de Toulouse, INRA, INP-ENVT, Toulouse, France, 4 Institut Claudius-Regaud, IUCT-Oncopole, Toulouse 5 Service des Maladies Infectieuses et Tropicales, CHU Toulouse, France ; 6 INSERM, UMR1043, Toulouse, France *Address for correspondence and reprint requests to Dr Peggy Gandia, Laboratoire de
Pharmacocinétique et Toxicologie, Centre Hospitalo-Universitaire Purpan, 330 avenue de Grande- Bretagne, 31059 Toulouse; E-mail: [email protected]; Tel:+33(0)567690383 ; Fax : +33 567690384
176
Supplementary data
ClH = fu x Clu Eq.1
and assuming ClH = Cltotal13,14
AUCtotal = Dose / fu x Clu Eq. 3
Where AUCtotal is the area under the curve for total plasma concentration over the dosing interval, τ,
Dose is the maintenance dosa and Clu is the unbound clearance corresponding to the intrinsic
metabolic capacities of hepatocytes.17 Thus the average total (measured) plasma concentration is:
Ct = AUCtotal / τ Eq. 4
Similarly
AUCunbound = Dose / Clu Eq. 5
And, Cu, the average unbound plasma concentration, in a steady-state condition is:
Cu= AUCunbound / τ Eq. 6
Where AUCunbound is the area under the curve for unbound plasma concentration over dosing interval,
τ, where 'Dose' is the maintenance dosage.
Thus, Eq.2 is extrapolated to the unbound trough concentration to explain the absence of modification to Cu if Clu remains unchanged.
Cu = Dose / Clu x τ Eq.2
Inspection of eqs. 5 and 6 shows that Clu, is the only factor that drives Cu (Eq. 2), and that Clu can
177
Annexe 2-11Article accepté dans Fundamental and Clinical Pharmacolgy portant sur l’étude
de la fraction libre de l’atazanavir chez des patients VIH.
Title: Is the unbound concentration of Atazanavir of interest in Therapeutic Drug Monitoring?
Running title: Exploration of Atazanavir unbound concentration.
David Metsu (PharmD) a,b, Patrick Seraissol (Biomedical Engineer) a, Pierre Delobel (MD, PhD)c, Christel Cinq-Frais (PharmD) d, Lize Cuzin (MD) e, Jacques Izopet (MD, PhD) f, Etienne Chatelut (PharmD,PhD) b, Peggy Gandia (PharmD, PhD) a,b
a Laboratoire de Pharmacocinétique et de Toxicologie, CHU Toulouse, France
b CRCT, Université de Toulouse, Inserm, UPS, Toulouse, France
c Service des Maladies Infectieuses et Tropicales, CHU Toulouse, France
d Laboratoire de Biochimie, CHU Toulouse, France
e COREVIH Midi-Pyrénées-Limousin, Toulouse, France
179
187