Effect of Carbamazepine on the Pharmacokinetics of Erdafitinib in Healthy Participants.

Erdafitinib, a selective and potent oral pan-FGFR inhibitor, is metabolized mainly through CYP2C9 and CYP3A4 enzymes. This phase 1, open-label, single-sequence, drug-drug interaction study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of erdafitinib alone and when co-administered with steady state oral carbamazepine, a dual inducer of CYP3A4 and CYP2C9, in 13 healthy adult participants (NCT04330248). Compared with erdafitinib administration alone, carbamazepine co-administration decreased total and free maximum plasma concentrations of erdafitinib (Cmax) by 35% (95% CI 30%-39%) and 22% (95% CI 17%-27%), respectively. The areas under the concentration-time curve over the time interval from 0 to 168 hours, to the last quantifiable data point, and to time infinity (AUC168h, AUClast, AUCinf), were markedly decreased for both total erdafitinib (56%-62%) and free erdafitinib (48%-55%). The safety profile of erdafitinib was consistent with previous clinical studies in healthy participants, with no new safety concerns when administered with or without carbamazepine. Co-administration with carbamazepine may reduce the activity of erdafitinib due to reduced exposure. Concomitant use of strong CYP3A4 inducers with erdafitinib should be avoided.

Prediction of Drug-Drug Interactions After Esketamine Intranasal Administration Using a Physiologically Based Pharmacokinetic Model.

BACKGROUND AND OBJECTIVE: A physiologically based pharmacokinetic (PBPK) modeling approach for esketamine and its metabolite noresketamine after esketamine intranasal administration was developed to aid the prediction of drug-drug interactions (DDIs) during the clinical development of esketamine nasal spray (SPRAVATO®). This article describes the development of the PBPK model to predict esketamine and noresketamine kinetics after intranasal administration of esketamine and its verification and application in the prediction of prospective DDIs with esketamine using models of index perpetrator and victim drugs. METHODS: The intranasal PBPK (IN-PBPK) models for esketamine/noresketamine were constructed in Simcyp® v14.1 by combining the oral and intravenous esketamine PBPK models, with the dose divided in the ratio 57.7/42.3. Verification of the model was based on comparing the pharmacokinetics and DDI simulations with observed data in healthy volunteers. RESULTS: The simulated and observed (171 healthy volunteers) plasma pharmacokinetic profiles of intranasal esketamine/noresketamine showed a good match. The relative contributions of different cytochromes P450 (CYPs), mainly CYP3A4 and CYP2B6, involved in esketamine/noresketamine clearance was captured correctly in the IN-PBPK model using the DDI clinical studies of intranasal esketamine with clarithromycin and rifampicin and a published DDI study of oral esketamine with ticlopidine. The induction potential of esketamine toward CYP3A4 was also well captured. Inhibition of intranasal esketamine in the presence of ticlopidine was predicted to be not clinically relevant. Different scenarios tested with esketamine as a CYP3A4 perpetrator of midazolam also predicted the absence of clinically relevant CYP3A4 interactions. CONCLUSION: This PBPK model of the intranasal route adequately described the pharmacokinetics and DDI of intranasal esketamine/noresketamine with potential perpetrator and victim drugs. This work was used to support regulatory submissions of SPRAVATO®.

Physiologically-based pharmacokinetic modeling to evaluate in vitro-to-in vivo extrapolation for intestinal P-glycoprotein inhibition.

As one of the key components in model-informed drug discovery and development, physiologically-based pharmacokinetic (PBPK) modeling linked with in vitro-to-in vivo extrapolation (IVIVE) is widely applied to quantitatively predict drug-drug interactions (DDIs) on drug-metabolizing enzymes and transporters. This study aimed to investigate an IVIVE for intestinal P-glycoprotein (Pgp, ABCB1)-mediated DDIs among three Pgp substrates, digoxin, dabigatran etexilate, and quinidine, and two Pgp inhibitors, itraconazole and verapamil, via PBPK modeling. For Pgp substrates, assuming unbound Michaelis-Menten constant (Km ) to be intrinsic, in vitro-to-in vivo scaling factors for maximal Pgp-mediated efflux rate (Jmax ) were optimized based on the clinically observed results without co-administration of Pgp inhibitors. For Pgp inhibitors, PBPK models utilized the reported in vitro values of Pgp inhibition constants (Ki ), 1.0 µM for itraconazole and 2.0 µM for verapamil. Overall, the PBPK modeling sufficiently described Pgp-mediated DDIs between these substrates and inhibitors with the prediction errors of less than or equal to ±25% in most cases, suggesting a reasonable IVIVE for Pgp kinetics in the clinical DDI results. The modeling results also suggest that Pgp kinetic parameters of both the substrates (Km and Jmax ) and the inhibitors (Ki ) are sensitive to Pgp-mediated DDIs, thus being key for successful DDI prediction. It would also be critical to incorporate appropriate unbound inhibitor concentrations at the site of action into PBPK models. The present results support a quantitative prediction of Pgp-mediated DDIs using in vitro parameters, which will significantly increase the value of in vitro studies to design and run clinical DDI studies safely and effectively.

Current Practices, Gap Analysis, and Proposed Workflows for PBPK Modeling of Cytochrome P450 Induction: An Industry Perspective.

The International Consortium for Innovation and Quality (IQ) Physiologically Based Pharmacokinetic (PBPK) Modeling Induction Working Group (IWG) conducted a survey across participating companies around general strategies for PBPK modeling of induction, including experience with its utility to address various questions, regulatory interactions, and regulatory acceptance. The results highlight areas where PBPK modeling is used with high confidence and identifies opportunities where confidence is lower and further evaluation is needed. To enhance the survey results, the PBPK-IWG also collected case studies and analyzed recent literature examples where PBPK models were applied to predict CYP3A induction-mediated drug-drug interactions. PBPK modeling of induction has evolved and progressed significantly, proving to have great potential to accelerate drug discovery and development. With the aim of enabling optimal use for new molecular entities that are either substrates and/or inducers of CYP3A, the PBPK-IWG proposes initial workflows for PBPK application, discusses future trends, and identifies gaps that need to be addressed.

Prediction of the drug-drug interaction potential of the α1-acid glycoprotein bound, CYP3A4/CYP2C9 metabolized oncology drug, erdafitinib.

Erdafitinib is a potent oral pan-fibroblast growth factor receptor inhibitor being developed as oncology drug for patients with alterations in the fibroblast growth factor receptor pathway. Erdafitinib binds preferentially to α1-acid glycoprotein (AGP) and is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. This article describes a physiologically based pharmacokinetic (PBPK) model for erdafitinib to assess the drug-drug interaction (DDI) potential of CYP3A4 and CYP2C9 inhibitors and CYP3A4/CYP2C9 inducers on erdafitinib pharmacokinetics (PK) in patients with cancer exhibiting higher AGP levels and in populations with different CYP2C9 genotypes. Erdafitinib's DDI potential as a perpetrator for transporter inhibition and for time-dependent inhibition and/or induction of CYP3A was also evaluated. The PBPK model incorporated input parameters from various in vitro and clinical PK studies, and the model was verified using a clinical DDI study with itraconazole and fluconazole. Erdafitinib clearance in the PBPK model consisted of multiple pathways (CYP2C9/3A4, renal, intestinal; additional hepatic clearance), making the compound less susceptible to DDIs. In poor-metabolizing CYP2C9 populations carrying the CYP2C9*3/*3 genotype, simulations shown clinically relevant increase in erdafitinib plasma concentrations. Simulated luminal and enterocyte concentration showed potential risk of P-glycoprotein inhibition with erdafitinib in the first 5 h after dosing, and simulations showed this interaction can be avoided by staggering erdafitinib and digoxin dosing. Other than a simulated ~ 60% exposure reduction with strong CYP3A/2C inducers such as rifampicin, other DDI liabilities were minimal and considered not clinically relevant.

Pediatric Pharmacokinetics and Dose Predictions: A Report of a Satellite Meeting to the 10th Juvenile Toxicity Symposium.

On April 24, 2019, a symposium on Pediatric Pharmacokinetics and Dose Predictions was held as a satellite meeting to the 10th Juvenile Toxicity Symposium. This symposium brought together scientists from academia, industry, and clinical research organizations with the aim to update each other on the current knowledge on pediatric drug development. Through more knowledge on specific ontogeny profiles of drug metabolism and transporter proteins, integrated into physiologically-based pharmacokinetic (PBPK) models, we have gained a more integrated understanding of age-related differences in pharmacokinetics (PKs), Relevant examples were presented during the meeting. PBPK may be considered the gold standard for pediatric PK prediction, but still it is important to know that simpler methods, such as allometry, allometry combined with maturation function, functions based on the elimination pathway, or linear models, also perform well, depending on the age range or the mechanisms involved. Knowledge from different methods and information sources should be combined (e.g., microdosing can reveal early read-out of age-related differences in exposure), and such results can be a value to verify models. To further establish best practices for dose setting in pediatrics, more in vitro and in vivo research is needed on aspects such as age-related changes in the exposure-response relationship and the impact of disease on PK. New information coupled with the refining of model-based drug development approaches will allow faster targeting of intended age groups and allow more efficient design of pediatric clinical trials.

Pharmacokinetic Drug-Drug Interaction of Apalutamide, Part 2: Investigating Interaction Potential Using a Physiologically Based Pharmacokinetic Model.

BACKGROUND: Apalutamide is predominantly metabolized via cytochrome P450 (CYP) 2C8 and CYP3A4, whose contributions change due to autoinduction with repeated dosing. OBJECTIVES: We aimed to predict CYP3A4 and CYP2C8 inhibitor/inducer effects on the steady-state pharmacokinetics of apalutamide and total potency-adjusted pharmacologically active moieties, and simulated drug-drug interaction (DDI) between single-dose and repeated-dose apalutamide coadministered with known inhibitors/inducers. METHODS: We applied physiologically based pharmacokinetic modeling for our predictions, and simulated DDI between single-dose and repeated-dose apalutamide 240 mg coadministered with ketoconazole, gemfibrozil, or rifampicin. RESULTS: The estimated contribution of CYP2C8 and CYP3A4 to apalutamide metabolism is 58% and 13%, respectively, after single dosing, and 40% and 37%, respectively, at steady-state. Apalutamide exposure is predicted to increase with ketoconazole (maximum observed concentration at steady-state [Cmax,ss] 38%, area under the plasma concentration-time curve at steady-state [AUCss] 51% [pharmacologically active moieties, Cmax,ss 23%, AUCss 28%]) and gemfibrozil (Cmax,ss 32%, AUCss 44% [pharmacologically active moieties, Cmax,ss 19%, AUCss 23%]). Rifampicin exposure is predicted to decrease apalutamide (Cmax,ss 25%, AUCss 34% [pharmacologically active moieties, Cmax,ss 15%, AUCss 19%]). CONCLUSIONS: Based on our simulations, no major changes in the pharmacokinetics of apalutamide or pharmacologically active moieties are expected with strong CYP3A4/CYP2C8 inhibitors/inducers. This observation supports the existing recommendations that no dose adjustments are needed during coadministration of apalutamide and the known inhibitors or inducers of CYP2C8 or CYP3A4.

Correction to: Pharmacokinetics, Safety and Tolerability of JNJ-56136379, a Novel Hepatitis B Virus Capsid Assembly Modulator, in Healthy Subjects.

In the original article Ninth and Tenth authors were incorrectly omitted from the author group. The correct author group is Joris Vandenbossche, Wolfgang Jessner, Maarten van den Boer, Jeike Biewenga, Jan Martin Berke, Willem Talloen, Loeckie De Zwart, Jan Snoeys, Koen Vandyck, John Fry, Jeysen Yogaratnam.

Effect of Fluconazole and Itraconazole on the Pharmacokinetics of Erdafitinib in Healthy Adults: A Randomized, Open-Label, Drug-Drug Interaction Study.

BACKGROUND AND OBJECTIVES: Erdafitinib, an oral selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The aim of this phase 1 study was to assess the pharmacokinetics and safety of erdafitinib in healthy participants when coadministered with fluconazole (moderate CYP2C9 and CYP3A inhibitor), and itraconazole (a strong CYP3A4 and P-glycoprotein inhibitor). The effect of CYP2C9 genotype variants (*1/*1, *1/*2, *1/*3) on the pharmacokinetics of erdafitinib was also investigated. METHODS: In this open-label, parallel-group, single-center study, eligible healthy adults were randomized by CYP2C9 genotype to receive Treatment A (single oral dose of erdafitinib 4 mg) on day 1, Treatment B (fluconazole 400 mg/day orally) on days 1-11, or Treatment C (itraconazole 200 mg/day orally) on days 1-11. Healthy adults randomized to Treatment B and C received a single oral 4-mg dose of erdafitinib on day 5. The pharmacokinetic parameters, including mean maximum plasma concentration (Cmax), area under the curve (AUC) from time 0 to 168 h (AUC168h), AUC from time 0 to the last quantifiable concentration (AUClast), and AUC from time 0 to infinity (AUC∞) were calculated from individual plasma concentration-time data using standard non-compartmental methods. RESULTS: Coadministration of erdafitinib with fluconazole increased Cmax of erdafitinib by approximately 21%, AUC168h by 38%, AUClast by 49%, and AUC∞ by 48% while coadministration with itraconazole resulted in no change in erdafitinib Cmax and increased AUC168h by 20%, AUClast by 33% and AUC∞ by 34%. Erdafitinib exposure was comparable between participants with CYP2C9 *1/*2 or *1/*3 and with wild-type CYP2C9 genotype. The ratio of total amount of erdafitinib excreted in the urine (inhibited to non-inhibited) was 1.09, the ratio of total amount of excreted metabolite M6 was 1.21, and the ratio of the metabolite to parent ratio in the urine was 1.11, when coadministration of erdafitinib with itraconazole was compared with single-dose erdafitinib. Treatment-emergent adverse events (TEAEs) were generally Grade 1 or 2 in severity; the most commonly reported TEAE was headache. No safety concerns were identified with single-dose erdafitinib when administered alone and in combination with fluconazole or itraconazole in healthy adults. CONCLUSION: Coadministration of fluconazole or itraconazole or other moderate/strong CYP2C9 or CYP3A4 inhibitors may increase exposure to erdafitinib in healthy adults and thus may warrant erdafitinib dose reduction or use of alternative concomitant medications with no or minimal CYP2C9 or CYP3A4 inhibition potential. TRIAL REGISTRATION: ClinicalTrials.gov identifier number: NCT03135106.

Pharmacokinetics, Safety and Tolerability of JNJ-56136379, a Novel Hepatitis B Virus Capsid Assembly Modulator, in Healthy Subjects.

INTRODUCTION: Hepatitis B viral capsid assembly is an attractive target for new antiviral treatments. JNJ-56136379 (JNJ-6379) is a potent capsid assembly modulator in vitro with a dual mode of action. In Part 1 of this first-in-human study in healthy adults, the pharmacokinetics (PK), safety and tolerability of JNJ-6379 were evaluated following single ascending and multiple oral doses. METHODS: This was a double-blind, randomized, placebo-controlled study in 30 healthy adults. Eighteen subjects were randomized to receive single doses of JNJ-6379 (25 to 600 mg) or placebo. Twelve subjects were randomized to receive 150 mg JNJ-6379 or placebo twice daily for 2 days, followed by 100 mg JNJ-6379 or placebo daily for 10 days. RESULTS: The maximum observed plasma concentration and the area under the curve increased dose proportionally from 25 to 300 mg JNJ-6379. Following multiple dosing, steady-state conditions were achieved on day 8. Steady-state clearance was similar following single and multiple dosing, suggesting time-linear PK. All adverse events (AEs) reported were mild to moderate in severity. There were no serious AEs or dose-limiting toxicities and no apparent relationship to dose for any AE. CONCLUSION: JNJ-6379 was well tolerated in this study. Based on the safety profile and plasma exposures of JNJ-6379 in healthy subjects, a dosing regimen was selected for Part 2 of this study in patients with chronic hepatitis B. This is anticipated to achieve trough plasma exposures of JNJ-6379 at steady state of more than three times the 90% effective concentration of viral replication determined in vitro. TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT02662712. FUNDING: Janssen Pharmaceutica.

A drug-drug interaction study of ibrutinib with moderate/strong CYP3A inhibitors in patients with B-cell malignancies.

This was an open-label, multicenter, phase-1 study to evaluate the drug interaction between steady-state ibrutinib and moderate (erythromycin) and strong (voriconazole) CYP3A inhibitors in patients with B-cell malignancies and to confirm dosing recommendations. During cycle 1, patients received oral ibrutinib 560 mg qd alone (Days 1-4 and 14-18), and ibrutinib 140 mg (Days 5-13; 19-27) plus erythromycin 500 mg tid (Days 5-11) and voriconazole 200 mg bid (Days 19-25). Twenty-six patients (median [range] age: 64.5 [50-88] years) were enrolled. Geometric mean ratio (90% confidence intervals) after co-administration of ibrutinib 140 mg with erythromycin and voriconazole was 74.7 (53.97-103.51) and 143.3 (107.77-190.42), respectively, versus ibrutinib 560 mg alone. The most common (≥20%) adverse events were diarrhea (27%) and neutropenia (23%). The results demonstrate that ibrutinib 140 mg with voriconazole or erythromycin provides exposure within the clinical range for patients with B-cell malignancies.

Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective.

This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted.

IMI - oral biopharmaceutics tools project - evaluation of bottom-up PBPK prediction success part 1: Characterisation of the OrBiTo database of compounds.

Predicting oral bioavailability (Foral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9L/h (interquartile range: 11.6-43.6L/h; n=23), volume of distribution was 80.8L (54.5-239L; n=23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed a median of 0.415 (0.203-0.724; n=22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.

Lipophilic nalmefene prodrugs to achieve a one-month sustained release.

Nalmefene is an opioid antagonist which as a once-a-day tablet formulation has recently been approved for reducing ethanol intake in alcoholic subjects. In order to address the compliance issue in this patient population, a number of potential nalmefene prodrugs were synthesized with the aim of providing a formulation that could provide plasma drug concentrations in the region of 0.5-1.0ng/mL for a one-month period when dosed intramuscular to dogs or minipigs. In an initial series of studies, three different lipophilic nalmefene derivatives were evaluated: the palmitate (C16), the octadecyl glutarate diester (C18-C5) and the decyl carbamate (CB10). They were administered intramuscularly to dogs in a sesame oil solution at a dose of 1mg-eq. nalmefene/kg. The decyl carbamate was released relatively quickly from the oil depot and its carbamate bond was too stable to be used as a prodrug. The other two derivatives delivered a fairly constant level of 0.2-0.3ng nalmefene/mL plasma for one month and since there was no significant difference between these two, the less complex palmitate monoester was chosen to demonstrate that dog plasma nalmefene concentrations were dose-dependent at 1, 5 and 20mg-eq. nalmefene/kg. In a second set of experiments, the effect of the chain length of the fatty acid monoester promoieties was examined. The increasingly lipophilic octanoate (C8), decanoate (C10) and dodecanoate (C12) derivatives were evaluated in dogs and in minipigs, at a dose of 5mg-eq. nalmefene/kg and plasma nalmefene concentrations were measured over a four-week period. The pharmacokinetic profiles were very similar in both species with Cmax decreasing and Tmax increasing with increasing fatty acid chain length and the target plasma concentrations (0.5-1.0ng/mL over a month-long period) were achieved with the dodecanoate (C12) prodrug. These data therefore demonstrate that sustained plasma nalmefene concentrations can be achieved in both dog and minipig using nalmefene prodrugs and that the pharmacokinetic profile of nalmefene can be tuned by varying the length of the alkyl group.

Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults.

AIMS: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is used in the treatment of mantle cell lymphoma or chronic lymphocytic leukaemia. Ibrutinib undergoes extensive rapid oxidative metabolism mediated by cytochrome P450 3A both at the level of first pass and clearance, which might result in low oral bioavailability. The present study was designed to investigate the absolute bioavailability (F) of ibrutinib in the fasting and fed state and assess the effect of grapefruit juice (GFJ) on the systemic exposure of ibrutinib in order to determine the fraction escaping the gut (Fg ) and the fraction escaping hepatic extraction (Fh ) in the fed state. METHODS: All participants received treatment A [560 mg oral ibrutinib, under fasting conditions], B (560 mg PO ibrutinib, fed, administered after drinking glucose drink) and C (140 mg oral ibrutinib, fed, with intake of GFJ before dosing). A single intravenous (i.v.) dose of 100 µg (13) C6 -ibrutinib was administered 2 h after each oral dose. RESULTS: The estimated 'F' for treatments A, B and C was 3.9%, 8.4% and 15.9%, respectively. Fg and Fh in the fed state were 47.0% and 15.9%, respectively. Adverse events were mild to moderate in severity (Grade 1-2) and resolved without sequelae by the end of the study. CONCLUSION: The absolute oral bioavailability of ibrutinib was low, ranging from 3.9% in the fasting state to 8.4% when administered 30 min before a standard breakfast without GFJ and 15.9% with GFJ. Ibrutinib was well tolerated following a single oral and i.v. dose, under both fasted and fed conditions and regardless of GFJ intake status.

Blood microsampling using capillaries for drug-exposure determination in early preclinical studies: a beneficial strategy to reduce blood sample volumes.

BACKGROUND: Capillary microsampling (CMS) of blood with subsequent blood analysis offers a potential strategy to deal with increased demand to reduce blood sample volumes in animal discovery and preclinical studies. RESULTS: A generic approach is presented allowing PK analysis in 15 µl blood samples. CMS blood exposure data were compared with the traditional plasma exposure results in rats and dogs. Blood PK profiles obtained for two different compounds were in agreement with profiles obtained in plasma. From these studies ex vivo blood to plasma ratios were also obtained. In a mouse study, blood PK profiles that were obtained following automatic sampling overlay with the blood PK profiles obtained with CMS. CONCLUSION: CMS in 15 µl glass capillaries allows collection and handling of small and exact volumes of blood. Although CMS can also be applied for plasma collection, the full benefit is only achieved with blood collection and analysis.

Postmortem redistribution of fentanyl in the rabbit blood.

Postmortem redistribution of fentanyl in the rabbit was investigated after application of the 50-µg/h Durogesic pain patch. Patches were applied for 48 hours. Two cycles of patch administration were used before characterization of the postmortem redistribution. Fentanyl showed marked redistribution into the femoral and pulmonary veins of the rabbit through 48 hours after the animals were humanely killed and the pain patches removed. The plasma concentration of 2.34 ng/mL in the femoral blood before killing the animals increased 5.6-fold by 48 hours after patch removal to 13.2 ng/mL. This postmortem concentration is approximately 3-fold the C(max) determined during antemortem pharmacokinetic analysis, 4 ng/mL, which was achieved 24 hours after the application of the second 50-µg/h Durogesic pain patch. After blood sampling for 48 hours after animal termination with patch removal compared with sampling for 48 hours from animals not terminated and with patch removal, the exposure ratios in the terminated animals were approximately 30-fold, indicating that between the postmortem redistribution of fentanyl and the cessation of hepatic clearance of fentanyl in the rabbit, the postmortem redistribution of fentanyl leads to an elevated measures of postmortem blood concentrations relative to antemortem blood concentrations.

Pharmacokinetics-pharmacodynamics of a respiratory syncytial virus fusion inhibitor in the cotton rat model.

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants, young children, elderly persons, and severely immunocompromised patients. Effective postinfection treatments are not widely available, and currently there is no approved vaccine. TMC353121 is a potent RSV fusion inhibitor in vitro, and its ability to reduce viral loads in vivo was demonstrated in cotton rats following prophylactic intravenous administration. Here, the pharmacokinetics of TMC353121 in the cotton rat, which is semipermissive for RSV replication, were further explored to build a pharmacokinetic-pharmacodynamic (PK-PD) model and to estimate the plasma drug levels needed for significant antiviral efficacy. TMC353121 reduced the viral titers in bronchoalveolar lavage fluid in a dose-dependent manner after a single subcutaneous administration and intranasal RSV inoculation 24 h after compound administration. The viral titer reduction and plasma TMC353121 concentration at the time of RSV inoculation were well described using a simple E(max) model with a maximal viral titer reduction (E(max)) of 1.5 log(10). The plasma drug level required to achieve 50% of the E(max) (200 ng/ml) was much higher than the 50% inhibitory concentration observed in vitro in HeLaM cells (0.07 ng/ml). In conclusion, this simple PK-PD approach may be useful in predicting efficacious exposure levels for future RSV inhibitors.