Mechanistic In Vitro Studies Indicate that the Clinical Drug-Drug Interaction between Telithromycin and Simvastatin Acid Is Driven by Time-Dependent Inhibition of CYP3A4 with Minimal Effect on OATP1B1

Abstract

A previous attempt to accurately quantify the increased simvastatin acid exposure due to drug-drug interaction (DDI) with coadministered telithromycin, using a mechanistic static model, substantially underpredicted the magnitude of the area under the plasma concentration-time curve ratio (AUCR) based on reversible inhibition of CYP3A4 and organic anion transporting polypeptide 1B1 (OATP1B1). To reconcile this disconnect between predicted and clinically observed AUCR, telithromycin was evaluated as a timedependent inhibitor of CYP3A4 in vitro, as well as an inhibitor of OATP1B1. Telithromycin inhibited OATP1B1-mediated [ 3 H]estradiol 17b-D-glucuronide (0.02 mM) transport with a mean IC 50 of 12.0 6 1.45 mM and was determined by IC 50 shift and kinetic analyses to be a competitive reversible inhibitor of CYP3A4mediated midazolam1-hydroxylation with a mean absolute inhibition constant (K i) value of 3.65 6 0.531 mM. The 2.83-fold shift in IC 50 (10.4-3.68 mM) after a 30-minute metabolic preincubation confirmed telithromycin as a time-dependent inhibitor of CYP3A4; the mean inhibitor concentration that causes half-maximal inactivation of enzyme (K I) and maximal rate of inactivation of enzyme (k inact) values determined for inactivation were 1.05 6 0.226 mM and 0.02772 6 0.00272 min 21 , respectively. After the integration of an enzyme time-dependent inhibition component into the previous mechanistic static model using the in vitro inhibitory kinetic parameters determined above, the newly predicted simvastatin acid AUCR (10.8 or 5.4) resulting from perturbation of its critical disposition pathways matched the clinically observed AUCR (10.8 or 4.3) after coadministration, or staggered administration, with telithromycin, respectively. These results indicate the time-dependent inhibition of CYP3A4 by telithromycin as the primary driver underlying its clinical DDI with simvastatin acid.

Inhibition and induction of CYP enzymes in humans: an update

“…(< 0.1?) (1) High Groll et al ( 2017 ), Krishna et al ( 2009 ) Indinavir Competitive 0.17–0.5 (> 0.16) High ☺ Nelfinavir Competitive 1–4.8 (> 1.4) Moderate (CYP2D6) ☺ Saquinavir Mechanism-based 0.65–2.99 (> 0.37) High ☺ Diltiazem Mechanism-based 2.2–5.0 (0.1–0.6) High ☺ Telithromycin Mechanism-based (competitive) 1.05 (3.65) (2.5) High Elsby et al ( 2019 ) Gestodene Mechanism-based 46 (0.02) High ☺ Palovaara et al ( 2000 ) Ceritinib Mechanism-based 0.16–0.2 (0.9–2.7) Moderate (2C9) Zhao et al ( 2020 ) Idelalisib Mechanism-based (metabolite) 5.1 (0.5–5) High Ramanathan et al ( 2016 ) Imatinib Competitive? 8 (1–4) Moderate O’Brien et al ( 2003 ) Lapatinib Mechanism-based 1.7 High (3A5: 37.6 uM) ...…”

Mechanistic in vitro studies indicate that the clinical drug–drug interactions between protease inhibitors and rosuvastatin are driven by inhibition of intestinal BCRP and hepatic OATP1B1 with minimal contribution from OATP1B3, NTCP and OAT3

“…Indeed, the use of mechanistic static equations for accurately predicting DDI has been applied successfully to 28 clinically observed statin DDIs with an accuracy of 97%, thereby proving the effectiveness of the approach for quantitative DDI prediction. 1 , 13 , 16 , 19 …”

“…The mean IC 50 (equating to K i ) values obtained for atazanavir, darunavir, lopinavir and ritonavir versus a range of transporters were incorporated into the adapted Rowland‐Matin mechanistic static equation (Equation 1 ) previously described by Elsby et al 1 , 13 , 19 in order to predict the change in rosuvastatin AUC based upon inhibition of an BCRP, OATP1B1, OATP1B3, NTCP, all combined hepatic transporter (OATP1B1/OATP1B3/NTCP; Equation 2 ), and OAT3 fraction excreted ( ƒ e ) value of 0.5, 0.38, 0.11, 0.21, 0.7 and 0.25, respectively. 13 Overall AUCR arising from multiple pathways, is simply the product (multiplication) of the AUCR determined for each separate ADME pathway, e.g., for combined inhibition of intestinal BCRP and hepatic OATP1B1, the overall AUCR is equal to the Equation 1 ‐derived AUCR for BCRP × the Equation 1‐derived AUCR for OATP1B1.…”

“…For inhibition of BCRP and of combined hepatic uptake as one process (e.g., OATP1B1+OATP1B3+NTCP), then it would be the Equation 1 ‐derived AUCR for BCRP × the Equation 2 ‐derived AUCR (combined OATP1B1+OATP1B3+NTCP). where K i = absolute inhibition constant (equating to IC 50 for transporters as the probe [S] <<<< K m in the transporter inhibition assay and assuming competitive inhibition, based on the Cheng‐Prusoff equation) 20 and [I] = unbound maximum hepatic inlet concentration (I in max u = f u × (C max + (((F a F g × k a × dose (mol))/Q h ))/R B )) for hepatic transporters, or [I] = maximum enterocyte concentration (I g = (F a F g × k a × dose (mol))/Q ent ) for intestinal transporters, 19 or [I] = unbound maximum plasma concentration at steady state (C max u = f u × C max ) for renal transporters. 19 f u = unbound fraction in plasma, C max = maximum total plasma concentration of inhibitor at steady state, F a F g = fraction of the dose absorbed after oral administration, k a = absorption rate constant (min −1 ), Q h = hepatic blood flow (1617 mL/min), R B is the blood‐to‐plasma concentration ratio (default = 1.0) and Q ent = enterocyte blood flow (300 mL/min).…”

Interaction potential between clarithromycin and individual statins—A systematic review

“…Our systematic literature search did not uncover an in vitro study examining clarithromycin's inhibition of CYP3A4 or BCRP using a statin as probe substrate. Using a mechanistic static model based on clarithromycin inhibitory kinetic parameters derived from multiple in vitro studies employing non‐statin probes, it has recently been estimated that inhibition of CYP3A4 represents the primary mechanism of clarithromycin's interaction with simvastatin (see Discussion for further details).…”