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PK and PD as predictors of clinical effect PKPD workshop at AGAH/Club Phase I •drug action – the interaction of the drug molecule at the binding site e.g. receptor, carrier, channel •drug effect – a measurable consequence of drug binding or drug action e.g. EEC change, QT prolongation •drug response – a desirable or undesirable clinical outcome e.g. reduced frequency of seizures, reduction in blood pressure 2 PKPD workshop at AGAH/Club Phase I How do we find and test new drugs? clinical preclinical ○ screening (empirical) ○ dose ranging (empirical) ○ molecular modeling ○ PKPD modeling ○ molecular design ○ optimal study design screening learning 3 design PKPD workshop at AGAH/Club Phase I …modeling may be understood as mechanized intuition applying the rules of – biology – logic – mathematics – statistics 4 PKPD workshop at AGAH/Club Phase I to learn from experience to develop models based on data………what data do we need? Preclinical: ◦ affinities of active drug molecules for the binding site (in vitro, in situ, in vivo) ◦ mechanism between binding and measurable effect including auto-regulation (feedback, synthesis) ◦ in vivo: dose(time) – concentration(time) – measurable effect(time) 5 PKPD workshop at AGAH/Club Phase I to learn from experience to develop models based on data………what data do we need? Clinical: ◦ ideally everything measured in the preclinical program (in vivo affinities will be difficult to obtain), but at least the following: dose(time) concentration(time) effect(time) ◦ in addition, drug response data as a function of time 6 PKPD workshop at AGAH/Club Phase I How can this strategy be incorporated into R&D planning? ◦ Every preclinical experiment and every clinical study is designed to add data to the PKPD knowledge base. ◦ The modeling and simulation (M&S) scientist participates in the project teams. ◦ For the M&S scientist there exists no boundary between preclinical and clinical development. The design route will prove to be faster than the “shortcut”. 7 PKPD workshop at AGAH/Club Phase I …from the work of EMF-Consulting: Example1 Selection of optimal doses for a new anti-epileptic drug to be tested in patients. M. Marchand1, O. Petricoul1, E. Fuseau1, D. Bentley2, D. Critchley2 1 EMF consulting, BP 2, 13545 Aix en Provence, France 2 EISAI Global Clinical Development, 3 Shortlands, London W6 8EE, UK ○ Rufinamide modulates the activity of sodium channels thus suppressing seizures induced by electroshock (maximal electroshock, MES) or by injection of pentylenetrazole (PTZ) in mice (PD). In clinical studies, rufinamide significantly reduced seizure frequency (PD). ○ Drug X is a new chemical entity with a novel mechanism of action. It shows anticonvulsant effects in rodents. The dose(time)-concentration(time) relationship (PK) was studied in epileptic patients. 8 PKPD workshop: Example 1 ○ PKPD modeling in mice: − Population PKPD modeling used NONMEM. − A one-compartment model with first order elimination was chosen for both rufinamide and Drug X. − For PKPD modelling, drug concentrations were predicted in male mice according to weight, the administered dose in mg/kg, population PK parameters (previously estimated), and time of test. 9 PKPD workshop: Example 1 PKPD modeling in mice – where are the problems? + mice are cheap + mice are genetically well defined + small interindividual variability − mice are small − difficult to dose accurately − difficult to obtain more than one blood sample 10 PKPD workshop: Example 1 PKPD modeling in mice – Population approach: Population PK model based on toxicokinetic data -free choice oral dosing (continuous input during dark hours) -oral dosing by gavage (controlled time of drug input) -blood sampling at steady state -blood sampling after single or multiple doses -destructive, only one sample per mouse -destructive, only one sample per mouse DR Cl/F = D·ka C(t)= Css 11 V/F·(ka – k) · (e -k·t −e -ka·t ) PKPD workshop: Example 1 PKPD modeling in mice – Population approach: Population PD model using predicted individual concentrations at the time of the effect measurement Individual concentrations are predicted based on: -the dose given at the PD experiment -the gender and weight of the mouse -the time of the effect measurement after the dose -the population PK model 12 PKPD workshop: Example 1 CONC Emax DV CONC C50 Emax = 100% (FIXED) C50 = 1.35 mg/mL = 5.98 % of mice protected from tonic hind limb seizure Rufinamide data: Observed and predicted % of protected mice from MES Test 100 80 60 40 20 Observations Predictions 0 0.0 0.5 1.0 1.5 2.0 Rufinamide concentrations (mg/mL) 13 2.5 3.0 PKPD workshop: Example 1 Rufinamide data: observed and predicted % of protected mice from PTZ Test CONC Emax CONC C50 Emax = 76.4% C50 = 1.64 mg/mL % of mice protected from clonic seizure DV 100 80 60 40 20 Observations Predictions 0 2 0 4 6 8 10 12 14 Rufinamide concentrations (mg/mL) 14 16 18 20 PKPD workshop: Example 1 CONC Emax DV CONC C50 Emax = 100% (FIXED) C50 = 141.6 ng/mL = 4.56 % of mice protected from tonic hind limb seizure Drug X data: observed and predicted % of protected mice from MES Test 100 Observations Predictions 80 60 40 20 0 0 50 100 150 Drug X concentrations (ng/mL) 15 200 250 PKPD workshop: Example 1 Drug X data: observed and predicted % of protected mice from PTZ Test Emax = 100% (FIXED) C50 = 88.1 ng/mL % of mice protected from clonic seizure CONC Emax DV CONC C50 100 Observations Predictions 80 60 40 20 0 0 50 100 150 200 Drug X concentrations (ng/mL) 16 250 300 PKPD workshop: Example 1 PKPD modeling in patients: Rufinamide: PD model based on clinical data Predicted total seizure frequency per 28 days 12 10 8 6 4 2 0 0 20 40 60 80 Cavss rufinamide concentrations (mg/mL) Log e (total seizure frequency) 0.893 0.0187 Cavss 17 100 PKPD workshop: Example 1 Link from mice to humans: assumes that the effective concentrations in mice are also effective in humans A generic mathematical link function (Weibull) was used to relate rufinamide preclinical effects to its clinical response (Loge of total seizure frequency over a period of 28 days). 18 PKPD workshop: Example 1 Predicted Loge (total seizure frequency per 28 days) Rufinamide preclinical effect (MES test): the link function shows that effective concentrations in the preclinical MES test are not effective clinically. Is the approach wrong? Not necessarily, but MES is definitely not a suitable preclinical test. -0.8 -1.0 -1.2 an ideal relationship: -1.4 50% protected mice are related to half the maximal reduction in seizure frequency in patients. -1.6 -1.8 -2.0 -2.2 -2.4 -2.6 -2.8 0 20 40 60 80 Predicted % of protected mice from tonic hind limb seizure 19 100 PKPD workshop: Example 1 Predicted Loge (total seizure frequency per 28 days) Rufinamide preclinical effect (PTZ test): the link function shows that concentrations which protect more than 50% of mice also reduce total seizure frequency per 28 days in patients. The relationship is not ideal but sensitive enough to be used for the following extrapolation (next slide). -0.8 Weibull Function -1.0 -1.2 -1.4 -1.6 -1.8 -2.0 -2.2 -2.4 -2.6 -2.8 0 20 40 60 80 Predicted % of protected mice from clonic seizure 20 100 PKPD workshop: Example 1 ○ Extrapolation from known to unknown: − assuming that the link between the preclinical and the clinical test is generally valid and independent of the pharmacologic agent used to cause the response, − the PTZ preclinical effect measurements of Drug X are used to predict total seizure frequency per 28 days (clinical response). 21 PKPD workshop: Example 1 Predicted Loge(total seizure frequency per 28 days) The link function is now applied to drug X: whatever drug X concentration is related to 70% of mice protected from seizures (PTZ test) is expected to be related to a clinical response of 28·e-1.3 =7.6 seizures in 28 days, a minimal response. 0 -1 -2 -3 -4 Answer: ~200ng/ml -5 -6 0 20 40 60 80 Predicted % mice protected from clonic seizure 22 100 PKPD workshop: Example 1 ○ Extrapolation from response to concentration: − the preclinical PD model for PTZ test of Drug X is used to predict the concentration in humans necessary to achieve a certain clinical response. − knowing… that for rufinamide the link function relates effective concentrations in mice to effective concentrations in humans. − assuming… that the link function has general applicability and is thus also valid for drug X. 23 PKPD workshop: Example 1 Drug X: Finding the necessary concentrations to achieve a certain total seizure frequency per 28 days (response) Predicted total seizure frequency per 28 days 12 10 8 6 4 2 0 0 50 100 150 200 250 Drug X concentrations (ng/mL) 24 300 350 PKPD workshop: Example 1 ○ Extrapolation from concentration to dose: − a PK model for Drug X established in epileptic patients in a phase IIa pilot study is used to predict the dosing regimen to produce the necessary concentrations. − this PK model takes the drug interaction with CYP3A4 inducers into account. The recommended dosage is stratified accordingly: 25 PKPD workshop: Example 1 In order to achieve similar decrease (2.8 per 28 days) of total seizure frequency as with a typical Cavss (15 μg/ml) of rufinamide, the following daily doses for Drug X are likely to produce a Cavss of 215 ng/mL: ○ Sub-population 1, without co-administration of CYP3A4 inducers: 1.8 units ○ Sub-population 1, with co-administration of CYP3A4 inducers: 7.7 units ○ Sub-population 2, without co-administration of CYP3A4 inducers: 4 units ○ Sub-population 2, with co-administration of CYP3A4 inducers: 15 units Note: a Cavss of 215 ng/mL was observed in healthy subjects following repeated daily doses of 4 units which were well tolerated. 26 PKPD workshop: Example 1 workshop…english atelier……..français Werkstatt…deutsch This is not a place to shop for work but a place to work. Before I go on to my second example I would like to solicit contributions, comments, anecdotes… from the attendees. 27 PKPD workshop at AGAH/Club Phase I …from the work of EMF-Consulting: Example 2 Selection of an optimal biomarker for neutral endopeptidase (NEP) inhibitors in humans. A.C. Heatherington, S. Sultana, R. Hidi, M. Boucher, E. Fuseau, M. Marchand, P. Ellis, S.W. Martin Pfizer Ltd, Sandwich, UK; EMF Consulting, Aix-en-Provence, France Objectives: ○ to select a reliable soluble biomarker for NEP inhibitors ○ to compare clinical PD models to in vitro PD models ○ to build a suitable PKPD model to optimally design future clinical studies 28 PKPD workshop: Example 2 Background: Neutral endopeptidase (NEP) is a metallopeptidase enzyme involved in the degradation of a number of endogenous peptides, including ○ vasoactive intestinal peptide (VIP) ○ substance P ○ endothelins (hydrolysis of big endothelin, Big ET-1, to endothelin) ○ atrial natriuretic peptide (ANP). It is hypothesized that NEP inhibitors would increase VIP leading to enhanced vasodilatation in genital tissues. Two molecules, UK-447,841 (in vitro IC50 10 nM) and UK-505,749 (in vitro IC50 1.1nM), have undergone pharmacological evaluation to assess their effect on plasma Big ET-1 and ANP levels. 29 PKPD workshop: Example 2 Studies: Double-blind, randomized, placebo-controlled phase 1 studies in healthy volunteers Design Dosing PK data PD data (big ET-1 and ANP) UK-447,841 Cross-over Parallel group Single escalating oral Multiple daily oral doses, doses, 100, 400 3 to 800 mg and 800 mg 14 samples up to 48 h 13 + 15 up to 48h 3 samples 7 samples up to 8h up to 12h 30 UK-505,749 Cross-over Single escalating oral doses, 0.1 to 540 mg 14 samples up to 48h 7 samples up to 12h PKPD workshop: Example 2 UK-447,841 median concentration (mg/L) median PK data, Phase I, healthy volunteers UK-447,841 100 3 mg 10 mg 30 mg 100 mg 200 mg 400 mg 800 mg 10 1 0.1 0.01 0.001 0.0001 0 10 20 30 Time (h) 31 40 50 PKPD workshop at AGAH/Club Phase I UK-505,749 median concentration (mg/L) median PK data, Phase I, healthy volunteers UK-505,749 100 0.1 mg 0.3 mg 1 mg 3 mg 10 mg 30 mg 90 mg 270 mg 540 mg 10 1 0.1 0.01 0.001 0 10 20 30 Time (h) 32 40 50 PKPD workshop: Example 2 Combined PKPD population model (NONMEM) for two drugs (PK) and two biomarkers (PD indirect response model for Big ET-1 and ANP) • the NEP inhibitors slow down the degradation (kout1,2) of Big ET-1 and ANP • Big ET-1 stimulates production rate (kin2) of ANP • ANP stimulates production rate (kin1) of Big ET-1 • age enhances production rate (kin2) of ANP • Emax , the maximum decrease in kout , is the same for both drugs but different for ANP (41%) and for Big ET-1 (66%) • age increases Emax for ANP • IC50, the drug concentration at half-maximal effect, if different for Big ET-1 and ANP and different for UK-505,749 and UK-447,841 • also in vivo UK-505,749 is 10 times more potent than UK-447,841 33 PKPD workshop: Example 2 PD indirect response model for Big ET-1 and ANP Pop PK model Cpred (447) Cpred (505) Pop PD model IC50 η (IIV) IC50 η (IIV) Emax kin1 η (IIV) kout1 BigET1 η (IIV) IC50 η (IOV) Emax 2 η (IIV) + kin2 ANP IC50 Age effect (+) kout2 η (IIV) Age effect (+) + (Emax C( 447 ) pred ) (Emax C( 505 ) pred ) k in k out 1 IC 50 ( 447 ) C( 447 ) pred IC50 ( 505 ) C( 505 ) pred 34 R Response compartment PKPD workshop: Example 2 10 Doses 3 to 800 mg of UK-447,841 Doses 0.1 to 540 mg of UK-505,749 Median Big ET-1 (pg/mL) 8 6 4 2 0 0 2 4 6 Time (h) 35 8 10 12 PKPD workshop: Example 2 140 Doses 3 to 400 mg of UK-447,841 Doses 0.1 to 540 mg of UK-505,749 Median ANP (pg/mL) 120 100 80 60 40 20 0 2 4 6 Time (h) 36 8 10 12 PKPD workshop: Example 2 12 Big Endothelin (pg/mL) 10 8 6 4 observed Big ET1 Population prediction of Big ET1 Individual prediction of Big ET1 2 0 0 2 4 6 8 10 12 UK-505,749 predicted concentration in effect compartment (mg/L) 37 14 PKPD workshop: Example 2 (3 to 800 mg) 14 after UK447,841 treatment BigE concentrations (pg/mL) 12 P5, P50 and P95 Sim P5, P50 and P95 Obs 10 8 6 4 2 0 0 5 10 15 Time (h) 38 20 PKPD workshop: Example 2 (0.1 to 540 mg) 14 after UK505,749 treatment BigE concentrations (pg/mL) 12 P5, P50 and 95 Sim P5, P50 and P95 Obs 10 8 6 4 2 0 0 2 4 6 Time (h) 39 8 10 12 PKPD workshop: Example 2 (3 to 400 mg) ANP concentrations (pg/mL) 250 after UK447,841 treatment 200 P5, P50 and P95 Sim P5, P50 and P95 Obs 150 100 50 0 0 2 4 6 Time (h) 40 8 10 12 PKPD workshop: Example 2 250 (0.1 to 540 mg) ANP concentrations (pg/mL) after UK505,749 treatment P5, P50 and P95 Sim P5, P50 and P95 Obs 200 150 100 50 0 0 2 4 6 Time (h) 41 8 10 12 PKPD workshop: Example 2 Conclusion ○ Big ET-1 plasma concentration and, to a lesser extent, ANP plasma concentration can be used as a pharmacological biomarker for the inhibitory drug effect on enzyme (NEP) activity in healthy volunteers. ○ Big ET-1 has ideal characteristics of a soluble biomarker: it demonstrates doseconcentration-effect, time-linearity, reproducibility of effect with similar Emax for two NEP inhibitors. ○ The ratio of the in vivo IC50 of the 2 compounds is similar to the in vitro ratio. This allows extrapolation between species and between different drugs. 42 PKPD workshop at AGAH/Club Phase I I hope to meet many of you again at the PAGE meeting in June 2007 in Copenhagen! 43