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Practically meeting modified release BE (bioequivalence) requirementsMR Bioequivalence Studiesinformalife sciences Defining study objectives Fasting / fed Single dose / multiple dose Reference product (MR / IR) Selecting CROs Protocol development Ethical considerations Assessing clinical andsafety laboratory facilities Selecting subjects Adhering to guidelinesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 2011DREAM…3

Practically meeting modified release BE (bioequivalence) requirementsMR Bioequivalence StudiesDefining study objectivesinformalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 20114REALITY…REALITY…REALITY…REALITY…Reference product (MR / IR)Reference product (MR / IR)Adhering to guidelinesAdhering to guidelinesEthical considerationsEthical considerationsProtocol developmentdevelopmentFasting / fedAssessing Assessing clinical clinical and safety safetylaboratory laboratory facilities facilitiesSelecting CROsSelecting CROsSingle dose / multiple multiple doseSelecting Selecting subjects

Practically meeting modified release BE (bioequivalence) requirementsSome topics…informalife sciencesBioequivalenceSurrogate of clinical equivalence orMeasure of pharmaceutical quality?Types of studiesPharmacokinetic (PK)Pharmacodynamic (PD)Clinical (equivalence and/or safety/efficacy)Healthy Subjects vs. patientsSingle dose vs. multiple doseParallel / cross-over / replicateInnovations in Modified Release | Evening Seminar | Berlin, 8 November 20115

Practically meeting modified release BE (bioequivalence) requirementsDesign IssuesSome topics…Reference product / batch, dose regimenFasted / fed state / food effectStandardizationNCA / PK (PD)Sampling scheduleMetrics (AUC, C max ; AUEC, Ae max , …)One size fits all? ⇒ Unconventional metricsDesign, methods, evaluationinformalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 20116

Practically meeting modified release BE (bioequivalence) requirementsAssumptionsWorld ‘Truth’αβModel ‘Data’H0HATheory ‘Reality’informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 20117

Practically meeting modified release BE (bioequivalence) requirementsModels vs. Realityinformalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 20118

Practically meeting modified release BE (bioequivalence) requirementsDefinition of BEEMA GL on BE (2010)Two medicinal products containing the sameactive substance are considered bioequivalentif they are pharmaceutically equivalent orpharmaceutical alternatives and their bioavailabilities(rate and extent) after administrationin the same molar dose lie within acceptablepredefined limits. These limits are set to ensurecomparable in vivo performance, i.e. similarityin terms of safety and efficacy.informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 20119

Practically meeting modified release BE (bioequivalence) requirementsModified releaseinformalife sciencesEMA (EUFEPS conference, Barcelona 2011)Modified release dosage forms are formulationswhere the rate and/or site of release of theAPI(s) is different from that of the conventional(IR) dosage form administered by the sameroute. This deliberate modification is achievedby special formulation design and/or manufacturingmethod. Prolonged release Delayed release Biphasic release Pulsatile releaseInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201110

Practically meeting modified release BE (bioequivalence) requirementsNCA vs. PK ModelingNoncompartmental methods do not rely on apharmacokinetic (=compartmental) modelAlso called SHAM (Shape, Height, Area,Moments)Metrics (plasma) Extent of absorption (EU…), total exposure (US): AUC Rate of absorption (EU…), peak exposure (US): C max t max (EU…) Early exposure (US, CAN): AUC t ; partial AUC truncatedmaxat population (CAN: subject’s) t max of the reference Others: C min , Fluctuation, MRT, Occupancy time, t lag ,…informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201111

Practically meeting modified release BE (bioequivalence) requirementsNCA vs. PK ModelingPharmacokinetic modelsUseful for understanding the drug/formulation Study design of BA/BE!Drawbacks: Almost impossible to validate (fine-tuning of sideconditions, weighting schemes, software, …) Still a mixture of art and science. Impossible to recalculate any given dataset using differentsoftware – sometimes even different versions of the samesoftware! Not acceptable for evaluation of BA/BE studies!informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201112

Practically meeting modified release BE (bioequivalence) requirementsNCA (Methods)informalife sciencesSingle doseCalculation of Moments of Curve (AUC t , MRT t ) Linear trapezoidal rule, loglinear trapezoidal rule, orcombination (lin-up, log-down).Calculation of half life (t ½ ) from elimination rate (λ z ) Unweighted (!) log-linear regressionExtrapolation from time point of last quantifiedconcentration to infinityCAUC = AUC + Cˆ∞ t or better AUCˆt= AUC +∞ tλˆtλC max / t max directly from profileInnovations in Modified Release | Evening Seminar | Berlin, 8 November 2011zz13

Practically meeting modified release BE (bioequivalence) requirementsSingle doseNCA (Methods)Method of estimation of λ z stated in protocol! One-compartment model: TTT-method *(Two times t max to t z ) Maximum adjusted R² (Phoenix/WinNonlin, Kinetica)22 (1 − R ) ⋅( n −1)WinNonlin ≤5.3:Radj= 1−n − 2 Multi-compartment models: starting point = last inflection Minimum AIC AIC = n ⋅ ln(2 ⋅ π ) + 1 + n ⋅ ln( RSS n) + 2⋅p[ ] Visual inspection of fit mandatory!C max includedPhoenix/WNL ≥6.0: C max excludedinformalife sciences* Scheerans C, Derendorf H and C KloftProposal for a Standardised Identification of the Mono-Exponential Terminal Phasefor Orally Administered DrugsBiopharm Drug Dispos 29, 145–157 (2008)Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201114

Practically meeting modified release BE (bioequivalence) requirementsNCA (Methods)100plasma profile (linear scale)80concentration604020informalife sciences00 4 8 12 16 20 24timeInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201115

Practically meeting modified release BE (bioequivalence) requirementsNCA (Methods)100plasma profile (semilogarithmic scale)concentration10C tCˆtinformalife sciences10 4 8 12 16 20 24timeInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201116

Practically meeting modified release BE (bioequivalence) requirementsSingle doseNCA (Methods)Unconventional parameters describingthe shape of profiles C max /AUC t 75% or POT-25 (Plateau Time: interval where C(t) ≥ 75% ofC max aka Peak Occupancy Time 25: time interval whereC(t) is within 25% of C max ) HVD or POT-50 (Half Value Duration, Peak OccupancyTime 50: time interval where C(t) ≥ 50% of C max ) Occupancy time, t ≥ MIC (time interval where C(t) is abovesome limiting concentration)informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201117

Practically meeting modified release BE (bioequivalence) requirementsNCA (Methods)100plasma profile (linear scale)80concentration604020informalife sciences00 4 8 12 16 20 24timeInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201118

Practically meeting modified release BE (bioequivalence) requirementsExcursion into PKAUC 72 vs. AUC ∞Bioequivalence assesses similarity of absorption(product specific) – not elimination (drug specific)Most suitable metric if k a < k el ?108i.v.ka = 8 × kelka = 4 × kel10concentrationinformalife sciences64200 12 24 36 48 60 72time (h)ka = 2 × kelka = kel (flip flop)ka = kel / 2ka = kel / 4ka = kel / 8Innovations in Modified Release | Evening Seminar | Berlin, 8 November 2011concentration10.10 12 24 36 48 60 72time (h)19

Practically meeting modified release BE (bioequivalence) requirementsExcursion into PKAUC 72 vs. AUC ∞V 10, D 100, F 100%, k el 0.08664 (t ½,el 8 h), k a 0.6931 h -1– 0.01083 h -1 (t ½,a 1 h – 64 h), AUC 0–∞ 115.42informalife sciencesλ zt ½PKAUC 0–72AUC 0–∞% extr. Bias (%)i.v.0.08664 8.0000 115.19 115.42 0.20

Practically meeting modified release BE (bioequivalence) requirementsExcursion into PKAUC 72 vs. AUC ∞Is it always justified to use AUC 72 (truncated AUC)as the primary PK metric for extent of absorption?No problems for IR formulations (k a≫k el ), sinceinformalife sciencesabsorption completed after 2–4×t maxControlled release may call for a different strategyGoing beyond flip flop PK (k a = k el ) the measuredAUC will mainly reflect elimination (drug specific);we don’t ‘see’ the absorption phase (formulationspecific)Little bias (+3%) even for k a = 8×k el if AUC ∞ is usedInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201121

Practically meeting modified release BE (bioequivalence) requirementsExcursion into PKAUC 72 vs. AUC ∞Cave! Absorption is completed if the formulationleaves the body – elimination only…1.0∞ abs.concentration0.80.60.40.2t=24t=36t=48t=60informalife sciences0.00 12 24 36 48 60 72time (h)Innovations in Modified Release | Evening Seminar | Berlin, 8 November 2011t=7222

Practically meeting modified release BE (bioequivalence) requirementsMultiple doseNCA (Methods)Calculation of AUC τ (dosage interval τ );AUC ss,24h if more than o.a.d. and chronopharmacologicalvariation)C ss,max directly from profileC ss,min from profile or better if missing values / timeˆ ( )deviations ˆ z tzC = C e −λτ −ss,minzPeak-Trough-Fluctuation (C ss,max – C ss,min ) / C ss,av ,where C ss,av = AUC τ / τSwing (C ss,max – C ss,min ) / C ss,minAUCF AUC above C ss,av / AUC τinformalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201123

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)informalife sciencesComparison of the shape of profilesf 1 ‘Difference factor‘; borrowed from dissolutiontestingf 1proportional to the average difference between thetwo profilesf1= 100 ⋅t=n∑t=1CR, t T , tt=n∑t=1R,tSuggested cut-off: Bioequivalent if f 1≤ 20* JW Moore and HH FlannerMathematical Comparison of curves with an emphasis on in vitro dissolution profilesPharm Tech 20/6, 64–74 (1996)Innovations in Modified Release | Evening Seminar | Berlin, 8 November 2011iC− Cii24

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)Comparison of the shape of profilesProblems with f 1Not a statistic!Value dependent on the location and number ofsampling time pointsUses differences (rather than ratios) ofconcentrations (additive instead of multiplicativemodel)Arbitrary cut-off (≤ 20) suitable?informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201125

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)Comparison of the shape of profilesξ i ‘Bioequivalence index’*∞⎛iC ( ) ( )0Rt − CTt ⎞ξ ⎜ ∫+i= ⎟ i ∈ N∞0 ≤ ξ i⎜ C ( ) ( )0Rt + CTti≤ 1⎟⎝ ∫⎠ ξ i = 0 if profiles are identical1i ξ i = 1 if one of the profiles shows only ‘zero’ valuesinformalife sciences* A RescignoBioequivalencePharm Res 9, 925–8 (1992)Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201126

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)Comparison of the shape of profilesξ i ‘Bioequivalence index’ Selection of i arbitrary (1 – 3 tried in literature) Approximation of by trapezoidal rule correct? Not a statistic Suggested cut-off: Bioequivalent if median ξ i ≤ 0.1 Generally ξ 1 < ξ 2 < ξ 3 ; meaning?∞∫0informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201127

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)informalife sciencesComparison of the shape of profilesMany more (or less esoteric) metrics suggested Chinchilli metric ψ Polli and McLean metrics (ρ, ρ m , δ a , δ s ) Karalis and Macheras metrics (MARD, MARD w1 , MARD w2 ) Percentage of the Common Area (PCA) Problems common with all profile metrics: identical timepoints assumed (time deviations, missing values?) No clear benefits; more research needed For an overview seeHA Bayoud and AM AwadPerformance of Several Bioequivalence Metrics for Assessing the Rate and Extent of AbsorptionJ Bioequiv Availab 3/7, 174–7 (2011)doi: 10.4172/jbb.1000080Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201128

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)MR valproic acid 500 mg o.a.d. fasting (n=20)concentration [µg/mL]1251007550250geometric means (n=20)testreference0 4 8 12 16 20 24time [h]concentration [µg/mL]concentration [µg/mL]125100755025012510075500 4 8 12 16 20 24time [h]25informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201100 4 8 12 16 20 24time [h]29

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)MR valproic acid 500 mg o.a.d. fasting (n=20)informalife sciencesmetricAUC τC maxC minMRT τ%PTFSwingpAUCFAUC95.6%94.0%94.1%98.6%76.4%67.9%87.7%73.0%90% CI105.9%102.3%109.3%101.7%106.1%104.3%122.3%100.5%Innovations in Modified Release | Evening Seminar | Berlin, 8 November 2011metric median BE criterionf 1 11.38 ≤20ξ 1 0.05535 ≤0.1ξ 2 0.06227 ≤0.1ξ 3 0.06660 ≤0.1ψ 0.7433 ≤1ρ 1.120 ≤1.4ρ m 0.1196 ≤0.35δ a 0.1086 ≤0.27δ s 0.01906 ≤0.102MARD 0.1218 ≤0.2MARD w1 0.1187 ≤0.2MARD w2 0.1668 ≤0.2PCA 0.8951 ≥0.8230

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)MR theophylline 400 mg o.a.d. fasting (n=24)concentration [µg/ml]2520151050geometric means (n=24)testreference0 4 8 12 16 20 24time [h]co n ce n tra tio n [µ g /ml ]co n ce n tra tio n [µ g /ml ]2 52 01 51 0502 52 01 51 050 4 8 1 2 1 6 2 0 2 4ti m e [h ]00 4 8 1 2 1 6 2 0 2 4ti m e [h ]informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201131

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)MR theophylline 400 mg o.a.d. fasting (n=24)informalife sciencesmetricAUC τC maxC minMRT τ%PTFSwingFAUC96.6%107.9%56.2%93.2%116.9%136.4%114.5%90% CI108.3%123.992.6%97.0%132.8%228.9%129.6%Innovations in Modified Release | Evening Seminar | Berlin, 8 November 2011metric median BE criterionf 1 17.53 ≤20ξ 1 0.08352 ≤0.1ξ 2 0.09176 ≤0.1ξ 3 0.09988 ≤0.1ψ 1.014 ≤1ρ 1.193 ≤1.4ρ m 0.1934 ≤0.35δ a 0.1086 ≤0.27δ s 0.3360 ≤0.102MARD 0.1920 ≤0.2MARD w1 0.1793 ≤0.2MARD w2 0.2891 ≤0.2PCA 0.8422 ≥0.8232

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)MR (IR+DR) methylphenidate 60 mg o.a.d. fed20Truncation time pointfor pAUC (4 h)concentration [ng/mL]15105t 75%HVDinter-/extrapolated valueslogarithmic trapezoidlinear trapezoidinformalife sciences94 96 98 100 104 108 112 120time [h]Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201133

Practically meeting modified release BE (bioequivalence) requirementsNCA (problems)informalife sciencesC minDefined by EMA as the concentration (C trough ) at theend of the dosing interval τCave: Not implemented in PK software (Phoenix/WinNonlin, Kinetica: C min = minimum concentrationwithin τ ). Requires adaption.As a single point metric even more variable thanC max (close to LLOQ if little accumulation).EMA requires pre-dose sampling at ≤–5 min andsampling at τ ±10 minIn a switch-over o.a.d. last sample 23:55 in P1 andat 24:00 in P2Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201134

Practically meeting modified release BE (bioequivalence) requirementsNCA (problems)C minMissing last samples may lead to ‘Apples-and-Oranges’ statistics (biased treatment effect)If a reliable estimate of λ z is possible (≥3 datapoints), we can use the estimate ± shift of C z according to λ z *ˆˆ z ( tz)= C e −λτ −(1)Css,minz Estimation independent from measured C z( Cˆ0− ˆ λz⋅ ( t0+ τ ))Cˆ = e (2)ss,mininformalife sciences* Gabrielsson J and D WeinerPharmacokinetic & Pharmacodynamic Data Analysis: Concepts and ApplicationsSwedish Pharmaceutical Press, Stockholm, p163 (4 th ed. 2006)Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201135

Practically meeting modified release BE (bioequivalence) requirementsNCA (problems)C minDR, flip flop PK; V 10, D 100, F 100%,k 0.09902 h -1R4(t ½ 7 h),t lag,R 1 h,3t lag,T 4 h,C max 3.68,2AUC 0–∞ 101.0concentrationT100 24 48 72informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 2011time36

Practically meeting modified release BE (bioequivalence) requirementsNCA (problems)C minCan we make a prediction about similarity offormulations in steady state from SD data (thusavoiding the required MD study)?Concentration at theMetric T Rintended dosage interval(here C 24 ) in dis-AUC 0–24 59.45 67.05t lag 4.00 1.00cussion (EUFEPS AUC 0–72 100.08 100.27NABarcelona 02/11 ,informa Berlin 11/11 )AUC 0–∞C 24101.052.7332101.032.3354C 720.08020.0622T / R0.88670.99791.00021.17031.2890T – R+3.00NANANANANAinformalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201137

Practically meeting modified release BE (bioequivalence) requirementsNCA (problems)C minSimulation of steady state (τ 24 h; 6 d ≈ 20×t ½ )R T R T654concentration321informalife sciences00 24 48 72 96 120 144Innovations in Modified Release | Evening Seminar | Berlin, 8 November 2011time38

Practically meeting modified release BE (bioequivalence) requirementsNCA (problems)C min‘Which’ C min reflects difference in formulations?concentration6543210RTTauCtrough (T)Ctrough (R)Cmin (global)concentration Global C min isidentical (2.682)! C trough is discriminatory:T 3.383R 2.850T/R 118.73% BTW: AUC τ andC max identical(linear PK)informalife sciences120 124 128 132 136 140 144Innovations in Modified Release | Evening Seminar | Berlin, 8 November 2011time39

Practically meeting modified release BE (bioequivalence) requirementsNCA (problems)informalife sciencesOnly C min ?But formulations differ in t lag ! Why use a surrogate?concentration6543210Tlag (R)Tlag (T)120 124 128 132 136 140 144Innovations in Modified Release | Evening Seminar | Berlin, 8 November 2011RtimeTTauconcentration t lag is discriminatory:T 4R 1T – R +3 Might be difficultto measure;frequent samplingrequired Nonparametricstatistics (EMA!)40

Practically meeting modified release BE (bioequivalence) requirementsNCA (problems)informalife sciencesOnly C min ?But formulations differ in t lag ! Why use a surrogate?concentration6543210Innovations in Modified Release | Evening Seminar | Berlin, 8 November 2011Tmax (R)Tmax (R)120 124 128 132 136 140 144RtimeTTauconcentration t max is discriminatoryas well:T 14.1R 11.1T – R +3 Maybe better;frequent samplingin the areaof C max usual Nonparametricstatistics (EMA!)41

Practically meeting modified release BE (bioequivalence) requirementsNCA (problems)informalife sciencesOnly C min ?But formulations differ in t lag ! Why use a surrogate?concentration6543210Innovations in Modified Release | Evening Seminar | Berlin, 8 November 2011MRT (R)MRT (T)120 124 128 132 136 140 144RtimeTTauconcentration C trough , t lag , andt max are singlepoint metrics;high variability! MRT uses theinformation of theentire profile; discriminatory?T 12.43R 11.64T – R +0.7842

Practically meeting modified release BE (bioequivalence) requirementsNCA (problems)EU GL 2010 (Section 4.1.8)A statistical evaluation of t max is not required.However, if rapid release is claimed to be clinicallyrelevant and of importance for onset of action or isrelated to adverse events, there should be noapparent difference in median t max and its variabilitybetween test and reference product.What’s this?How to assess that?‘A non-parametric analysisis not acceptable.’informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201143

Practically meeting modified release BE (bioequivalence) requirementsNCA (problems)PK metrics which are not continous, butsampled from a discrete distribution (t max , t lag )must (!) be evaluated by a nonparametricmethodEspecially for delayed release formulations it ishypocritical to require a surrogate (C min ) – insteadassessing the metric causing the formulations’difference (t lag )It’s high time for EMA to reconsider their idiosyncrasiestowards well-established statistical methodsinformalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201144

Practically meeting modified release BE (bioequivalence) requirementsNCA (problems)informalife sciencesCan we make a prediction about similarity offormulations in steady state from SD data(avoiding the MD study)?Concentration at the intended dosage interval(e.g., C 24 ) in discussion (EUFEPS Barcelona 2011)C z is dependend on all formulation-specific PKparameters (F, k a , t lag )No direct correlation between C z and accumulationratioAccumulation depends only on the amount of drugremaining in the body at the next administration(expressed as AUC 0–∞ – AUC 0–t )Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201145

Practically meeting modified release BE (bioequivalence) requirements543210NCA (problems)CR formulation, flip flop PK, D 100, V 5,F R 100%, F T 95%, k el 0.231 h -1 (t ½ 3 h),k a,R 0.0693 h -1 (t ½ 10 h), k a,T 0.0815 h -1 (t ½ 8.5 h)CR, f lip-f lop PK ( k a < k e l )TestRef erence0 4 8 12 16 20 24C zMetricC maxAUC 0–24AUC 0–∞AUC 24–∞extrapol.T3.80064.4582.8818.4322.2%1.424R3.58163.2787.4324.1527.6%1.590T / R106.1%101.9%94.8%76.3%NA89.5%80 –125%passpasspassfailNApassinformalife sciences Common metrics (and C z ) pass – but will Test accumulate lessthan Reference and fail in steady state (predicted by AUC 24–∞ )?Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201146

Practically meeting modified release BE (bioequivalence) requirementsNCA (problems)CR formulation, flip flop PK, absorptioncompleted after 36 hours)54TestRef erenceCR, f lip-flop PK ( k a < k e l ; absorption completed af t er 36 h)MetricC maxT4.659R4.591T / R101.5%80 –125%pass3AUC 0–τ77.8679.4298.0%pass21informalife sciences00 24 48 72 96 120 Common metrics pass; C max is less sensitive to detect differencesin steady state (101.5%) than after a single dose (106.1%) Know your formulation! Prediction based on C z removed from MR draft (Berlin 11/2011)Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201147

Practically meeting modified release BE (bioequivalence) requirementsNCA (example)MR (IR+DR) methylphenidate 60 mg o.a.d. fed100Estimation of λ z by semilogarithmicregressionconcentration [ng/mL]101Estimation of AUC τ andC min if last time pointnot exactly at t=τC z 0.232C min 0.228 (1)C min 0.205 (2)0.2informalife sciences94 96 98 100 104 108 112 120time [h]Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201148

Practically meeting modified release BE (bioequivalence) requirementsNCA (example)MR (IR+DR) methylphenidate 60 mg o.a.d. fed100concentration [ng/mL]101Estimation of AUC τ andC min if sample at t=τ ismissingC z 0.917C min 0.131 (1)C min 0.137 (2)0.2informalife sciences94 96 98 100 104 108 112 120time [h]Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201149

Practically meeting modified release BE (bioequivalence) requirementsNCA (example)MR (IR+DR) methylphenidate 60 mg o.a.d. fed3concentration [ng/mL]10.50.2C z 0.917C min 0.131 (1)C min 0.137 (2)informalife sciences0.1112 114 116 118 120time [h]Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201150

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)Partial AUC (pAUC) for multiphasic profilesTruncated AUC (at a time point based on clinicalconsiderations)First pAUC describes early onset,second pAUC maintenance of levels Examples: Zolpidem ER, Methylphenidate SR/ER First guidance on Zolpidem issued in 2009AUC 0–1.5 (~ sleep onset)AUC 1.5–t (~ sleep maintenance)AUC 0–∞ , C maxinformalife sciencesFDA (Office of Generic Drugs, CDER)Draft Guidance on ZolpidemAugust 2009http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM175029.pdfInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201151

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)pAUC for multiphasic profiles ER Zolpidem: AUC 0–1.5 may be highly variable; scaling?(not acceptable for EMA!)N7237parameterC maxAUC 0–1.5AUC 1.5–tAUC 1.5–∞AUC 0–∞PE1.02 1.22–0.96 0.99CV intra 25% 65%–27% 25%(90% CI) (0.96 – 1.10) (1.01 – 1.46)(0.89 – 1.04) (0.92 – 1.06)PE(90% CI) –0.93(0.85 – 1.03)1.13(1.04 – 1.23) –CV intra 26% 21%informalife sciencesMidha KK and G McKayUse of Partial Area Under the Curve for BE Assessment of Products with Complex PK Profiles; a View PointMeeting of the Pharmaceutical Science and Clinical Pharmacology Advisory Committee, April 13, 2010http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM209320.pdfInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201152

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)informalife sciencespAUC for multiphasic profiles Methylphenidate SR/ER In fasting subjects the IR’s t max is 2 ± 0.5 h ( x ± SD) 2 hours is also time at which maximal responsecompared to placebo is achieved By 3 hours, expected that 95 % of patients shouldachieve maximal early onset of response (sincex + 2×SD = 95 % of population) Food delays IR absorption by about one hour Truncation time point for pAUC in fed state therefore is3 + 2×0.5 = 4 hoursBM Davit (Acting Director Division of Bioequivalence 2, Office of Generic Drugs, OPS/CDER/FDA)Use of Partial AUC: Case Studies and BE ApproachesMeeting of the Pharmaceutical Science and Clinical Pharmacology Advisory Committee, April 13, 2010http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM209320.pdfInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201153

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)pAUC for multiphasic profiles Methylphenidate SR/ER Various formulations on the market; hybrid applications(PK + clinical data) Not interchangeable; differences in AUC 0–4 (fed state)studyRitalin LA vs. Medikinet ret. 1Equasym Ret. vs. Medikinet ret. 2AUC 0–4(PE, 90% CI)0.804 (0.732 – 0.882)0.829 (0.726 – 0.947)CV intra(%)19.819.0informalife sciences1 Haessler F, Tracik F, Dietrich H, Stammer H and J KlattA pharmacokinetic study of two modified-release methylphenidate formulations under differentfood conditions in healthy volunteersInt J Clin Pharmacol Ther 46/9, 466–76 (2008)2 Schütz H, Fischer R, Großmann M, Mazur D, Leis HJ and R AmmerLack of bioequivalence between two methylphenidate extended modified release formulationsin healthy volunteersInt J Clin Pharmacol Ther 47/12, 761–9 (2009)Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201154

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)pAUC for multiphasic profiles Methylphenidate SR/ER Although BE, variabilityof AUC 0–4(≈20%) higher thanof conventional PKmetrics; typical:AUC t 7% – 12%C max 10% – 15%% Reference17515012510075Methylphenidate 20mg MR SD fed (sprinkled vs. intact)90% CIPE500 4 8 12 16pAUC 0-t (cut-off in hours)informalife sciencesFischer R, Schütz H, Grossmann M, Leis HJ, and R AmmerBioequivalence of a methylphenidate hydrochloride extended-release preparation:comparison of an intact capsule and an opened capsule sprinkled on applesauceInt J Clin Pharmacol Ther 44/3, 135-141 (2006)Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201155

Practically meeting modified release BE (bioequivalence) requirementsNCA (alternative metrics)pAUC for multiphasic profiles Methylphenidate SR/ER Variability of early pAUC reproducible between studiesCV intra (%)806040Methylphenidate MR fed20/30mg SD pilot20mg SD pivotal20mg SD sprinkled vs. intact60mg SD60mg MD20informalife sciences00 4 8 12 16 20 24pAUC 0-t (cut-off in hours)Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201156

Practically meeting modified release BE (bioequivalence) requirementsSampling at C maxinformalife sciencesWith any (!) given sampling scheme the ‘true’C max is missedIt is unlikely that we sample exactly at the trueC max for any given subjectHigh inter- and/or intra-subject variability (singlepoint metric)Variability higher than AUC’sIn many studies the win/loose metric!Try to decrease variability Increase sample size (more subjects) Increase sampling within each subject (maybe better)Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201157

Practically meeting modified release BE (bioequivalence) requirementsSampling at C maxinformalife sciencesTheoretical values (from PK simulation)C max : 41.9/53.5 (81.2%), t max : 6.11/4.02 (∆ 2.09)# samples [2–12h] n = 4 C max 78.3% t max ∆ 4 n = 5 C max 78.3% t max ∆ 4 n = 6 C max 79.8% t max ∆ 1 n = 7 C max 81.2% t max ∆ 2Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201155453525R theoreticalT theoreticalR sampledT sampled0 3 6 9 1258

Practically meeting modified release BE (bioequivalence) requirementsSampling at C max‘C max was observed within two to five hoursafter administration …’Elimination is drug specific,but what about absorption?Formulation specific (k aand/or t lag)!Dependent on the sampling schedule (in a strictsense study-specific)informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201159

Practically meeting modified release BE (bioequivalence) requirementsSampling at C max5040302–5 hrsk a = [0.182 | 0.260]arithmetic meangeometric meanmedian2010informalife sciences00 4 8 12 16 20 24Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201160

Practically meeting modified release BE (bioequivalence) requirementsSampling at C max50402–5 hrsarithmetic meangeometric meanmedian30k a = 0.182t lag = [0 | 2.5]2010informalife sciences00 4 8 12 16 20 24Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201161

Practically meeting modified release BE (bioequivalence) requirementsAnother ProblemEMA GL on BE (2010)Section 4.1.8 Reasons for exclusion 1) A subject with lack of any measurable concentrations oronly very low plasma concentrations for referencemedicinal product. A subject is considered to have verylow plasma concentrations if its AUC is less than 5% ofreference medicinal product geometric mean AUC (whichshould be calculated without inclusion of data from theoutlying subject). The exclusion of data […] will only beaccepted in exceptional cases and may question thevalidity of the trial.Remark: Only possible after unblinding!informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201162

Practically meeting modified release BE (bioequivalence) requirementsAnother ProblemEMA GL on BE (2010)Section 4.1.8 Resons for exclusion 1) cont’d The above can, for immediate release formulations, be theresult of subject non-compliance […] and should as far aspossible be avoided by mouth check of subjects afterintake of study medication to ensure the subjects haveswallowed the study medication […]. The samples fromsubjects excluded from the statistical analysis should stillbe assayed and the results listed.informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201163

Practically meeting modified release BE (bioequivalence) requirementsAnother Probleminformalife sciencesGastro-resistant (enteric coated) preparationsGastric emptying of single unit dosage formsnon-disintegrating in the stomach is prolongedand highly erratic. The consequences of thiseffect on the enteric coating of delayed releaseformulations are largely unpredictable. Sampling period should be designed such that measurableconcentrations are obtained, taking into consideration notonly the half-life of the drug but the possible occurrence ofthis effect as well. This should reduce the risk of obtainingincomplete concentration-time profiles due to delay to themost possible extent. These effects are highly dependenton individual behaviour.Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201164

Practically meeting modified release BE (bioequivalence) requirementsAnother Probleminformalife sciencesGastro-resistant (enteric coated) preparations Therefore, but only under the conditions that samplingtimes are designed to identify very delayed absorption andthat the incidence of this outlier behaviour is observed witha comparable frequency in both, test and reference products,these incomplete profiles can be excluded fromstatistical analysis provided that it has been considered inthe study protocol.EMEA, CHMP Efficacy Working Party therapeutic subgroupon Pharmacokinetics (EWP-PK)Questions & Answers: Positions on specific questions addressed to the EWP therapeuticsubgroup on PharmacokineticsEMEA/618604/2008 Rev. 3, 26 January 2011http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002963.pdfWhat is ‘comparable’? For a study in 24 subjects, we get asignificant difference for 5/0 (Fisher’s exact test: p 0.0496).Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201165

Practically meeting modified release BE (bioequivalence) requirementsCase Study (PPI)informalife sciencesAttempt to deal with high variability in C maxPowered to 90%according to CVfrom previousstudies; 140 (!)subjects and to80% for expecteddropout rate.Sampling every30 min up to14 hours(7,785 total).t max 15 h, C max 3.5×LLOQ15005002505025Innovations in Modified Release | Evening Seminar | Berlin, 8 November 20115First time C maxt ½ 12 h0 4 8 12 16 20 24t lag 6 htime (h)66

Practically meeting modified release BE (bioequivalence) requirementsDrug specific, but …Half livesThe apparent elimination represents the slowestrate constant (controlled release, topicals,transdermals) – not necessarily elimination!Avoid the term ‘terminal elimination’ –might not be trueImportant in designing studies To meet AUC t ≥ 80% AUC ∞ criterion To plan sufficiently long wash-out (avoid carry-over) To plan saturation phase for steady stateinformalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201167

Practically meeting modified release BE (bioequivalence) requirementsHalf livesDealing with literature dataWhat if only mean ±SD is given? Assuming normal distribution:µ ± σ covers 68.27% of values (15.87% of values areexpected to lie outside of µ ± σ) Example: 8.5 ± 2.4 hours, 36 subjects.0.1587 × 36 = 5.71 or in at least five subjects we mayexpect a half life of > 10.9 hours. Plan for 95% coverage (z 0.95 = 1.96): p 0.95 = µ ± z 0.95 × σ8.5 ± 1.96 × 2.4 = [3.80, 13.2] hours.We may expect a half life of >13.2 hours in ~one subject(0.05/2 × 36 = 0.90).informalife sciencesInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201168

Practically meeting modified release BE (bioequivalence) requirementsHalf lives755010010µ 1.96σµ − 1.96σµ µ − σµµ µ + σµ + 1.96σµ σµ + 1.96σ2510 12 24 36 48informalife sciences00 12 24 36 48Innovations in Modified Release | Evening Seminar | Berlin, 8 November 201169

Practically meeting modified release BE (bioequivalence) requirementsCongratulations!Practically meeting modifiedrelease BE requirementsOpen Questions?informalife sciencesHelmut SchützBEBACConsultancy Services forBioequivalence and Bioavailability Studies1070 Vienna, Austriahelmut.schuetz@bebac.atInnovations in Modified Release | Evening Seminar | Berlin, 8 November 201170

Practically meeting modified release BE (bioequivalence) requirementsTo bear in Remembrance...You should treat as manypatients as possible withthe new drugs while theystill have the power to heal.Armand TrousseauGuidelinesare guidelinesare guidelines.Henrike Potthastinformalife sciences[…] our greatest mistakewould be to forget thatdata is used for seriousdecisions in the very realworld, and bad informationcauses suffering and death.Ben GoldacreInnovations in Modified Release | Evening Seminar | Berlin, 8 November 2011It is a good morningexercise fora research scien-tist to discard apet hypothesisevery day before breakfast.It keeps him young.Konrad Lorenz71