IVIVC Perspective, Generic Pharmaceuticals - PQRI

Simulation-based development• ‘Biorelevant Dissolution’ modeling wasdeveloped to predict and optimize an MRrelease profile.– Applied to slow/fast releasing profiles, based onfirst and/or zero order inputs, convoluted basedon PK information to predict plasma profiles.– Adapted to a number of MR technologies,including OROS-based formulations.

Proof of Concept• IVIVC seems to have sprung as a proof-ofconceptthat biorelevant dissolution-baseddevelopment worked.• Lew Leeson’s work from these efforts naturallygave rise to championing application of IVIVCin drug development.• Today, we continue the generation of theseapplications.

Simulation• Simulate plasma profiles based on releaseprofiles & knowledge of PK, to theoreticallyoptimize delivery.• Simulate plasma levels, based on In Vitro input,for correlation with In Vivo data and/or supportvalidation of IVIVC?• Simulate the Disso Environ for correlation with InVivo?…. How can this help drug development.

Rationale for IVIVC• Justify (validate?) dissolution testing methodas a quality control tool demonstratingrelevance of dissolution specifications to invivo performance (‘biorelevance’).• Surrogate to bioavailability studies,– May assist in guiding formulation development– May support SUPAC• Current Regulations require validation;therefore, this discussion is largely a reflectionof IVIVRs (i.e. IVIV Relationships).

How do we really simulate…This?With This?Source: Google Images

Possible Ways to Approach IVIVC

Possible Ways to Approach IVIVCSimulation and POC

Possible Ways to Approach IVIVCDevelopment of IVIVC

Possible Ways to Approach IVIVCDevelopment of IVIVCValidation of IVIVC

Favorability of IVIVR for MRHigherBCS 1OROSFavorabilityLowerBCS 2BCS 3BCS 4- pH-sensitivepolymers- gastric emptyingeffects & otherfood effects- Beads or Tablets?BCS of APIRobustness ofRelease Mechanism

Some Assumptions for Ideal IVIVR• Application suited to MR formulations, owing torelease rate-limited absorption• In vitro release characterization is relevant toobservations of absorption in vivo (biorelevance)• Formulation is robust to in vivo perturbations,ex. physiologic pHs, agitation, food-effects• API more typically of the BCS1 characteristics.• ADME not too complex; ex.: Kinetics linear overrange of doses evaluated, Absorption over lengthof GIT, limited influence of transporters.

A Word About Variability• Complexity of ADME may have someinherent error that would need to be factoredin, for purposes of data interpretation.• Error due to formulation should beconsidered.– Ex. consider Paroxetine, IR vs ER,the ER is clearly more variable, but is a result inboth effect of ADME and formulation errors.

Lopressor OROS, example• Metoprolol Fumarate, metoprolol regarded asa model BCS1.• OROS formulation appears to be an ‘ideal’type of formulation suited for IVIVC.• However, this type of formulation is probablya relatively rare occurrence, in general.

Lopressor Oros, Insensitive to changesin In Vitro conditionsdissolutioninsensitive to:- Multiple pHs ,1-8- Agitation rates- Addition ofsurfactantSource: Lopressor OROS Summary Basis of Approval

Lopressor Oros, IVIV Relationship- BCS 1 drugSource: Lopressor OROS Summary Basis of Approval

Lopressor Oros,SBA Biopharm notes:• The firm has developed a PK model whichpredicts metoprolol in vivo data using the in vitrodissolution data of the metoprolol OROSformulations.• Simulations based on +/- 2.5 SD of dissolutionvalues were compared to actual plasma levels ofthe BA/BE batches.Source: Lopressor OROS Summary Basis of Approval

Lopressor Oros,Biopharm conclusions:• The results showed a very good correlation between in vitrodissolution and the in vivo steady-state profile.• There was, however, no information in the submission that‘validates’ the model developed by the firm.• Evaluation of the six bio-lots showed the range of % dissolutionfor the six lots at 3, 6, 12 and 24hr. Based on these findingsand the additional support provided by the simulations, thedissolution specifications proposed by the firm wereconsidered acceptable.Source: Lopressor OROS Summary Basis of Approval

Barriers to IVIVC• Low solubility API (ex. disso may require SLS)– Is In Vitro data Biorelevant?• How to deal with food effects– Expect a robust formulation performance ?– Adapt a separate In Vitro system for food data ?• Compounded sources of variability– In Vivo > > In Vitro, typically …. Result of addedbiological variation and/or formulation variation?

Voltaren XR, Limited IVIV Relationship- pH-sensitive BCS2 drug MR• Diclofenac Na, pKa ~4, limited solubility underacidic conditions, considered BCS2.• The inactive ingredients in Voltaren-XRinclude: cetyl alcohol, hydroxypropylmethylcellulose, iron oxide, magnesiumstearate, polyethylene glycol, polysorbate,povidone, silicon dioxide, sucrose, talc,titanium dioxide.

Voltaren XR, Limited IVIV Relationship- Food EffectSource: Voltaren XR Summary Basis of Approval

IVIVR Limitations(Voltaren XR example)FDA request: IVIVCs are desirable for SR formulations as qualitycontrol and to set dissolution specifications.Sponsor: IVIVCs were evaluated.The data indicated absorption was dependent on gastricemptying time, which may be generally attributed to relateddifferences in fed or fasted states.IVIVC based on deconvolution was generally good in fasted state.The corresponding data from fed state did not correlate well within vitro results.Source: Voltaren XR Summary Basis of Approval

IVIVR Differences Expected for Fasted & FedConditions, when Food-effects are seenFasting CorrelationFed CorrelationSource: In Vitro In Vivo Relationships, Young, Devane &Butler, Eds.; Chapter 1, by Rackley, 1997.

Dissolution Conditions were Identified toMatch In Vitro to In Vivo, improving IVIVRWhile dissolution can be modified to mimic fed conditions,correlation may improve. But, the utility in developmentprocess may be limited.Source: In Vitro In Vivo Relationships, Young, Devane &Butler, Eds.; Chapter 1, by Rackley, 1997.

Generic IVIVC Perspective- VisionSource:Google Imagesfor Holy Grail

Reality- Many attempts in earnest,but only few with limited successSource: Google Images for Holy Grail

Generic Industry– Practical Application• Validating IVIVC not typically or formally done,as benefit vs investment is uncertain.• IVIVR Concepts, however, may be investigatedto support fine-tuning formulation to match atarget.• Level A rarely used, sometimes for simulationsbased on very limited assumptions.• Level C more commonly investigated, basedon primary PK parameters for BE.

Process for IVIVC-based Development• Decide how you will bracket your target– Simulation-based (rare)– Dissolution-based (common)• Manufacture at least 2 prototypes bymanipulating one (or more) elements of theformulation or process• Test Prototypes In Vivo– Interpret results based on Primary PK BE parametersand refine Test Formulation toward a PivotalFormulation.

Presumed Correlations ?- Alcohol Dose-Dumping Requirements• Due to increased concerns over dose-dumping inpresence of alcohol, in vitro testing isrecommended for some MR products, which mayhave potential toxicity implications.• Standard screen includes challenge in dissolutionmedia, with increasing levels of alcohol (ex. 5%,20%, 40%) to simulate release In Vivo.• In Vitro characterization may not always bepredictive of In Vivo performance (as is often thecase with ‘assumed’ IVIVRs).

Lack of Confirmed Relationship... In vitro and In vivo alcohol dose dumpingStudy TypeIn VitroDoseDumpingIn VivoDoseDumpingPalladoneXL(Hydromorphone)Kadian(MorphineSulfate)Opana ER(Oxymorphone)Yes Yes NoYes No YesIn Vivo testing has been used to confirm presenceor absence of alcohol dose-dumping effects.

Closing Thoughts on IVIVC• IVIVCs are product specific,– Applicable to specific variations within MR formulation– BCS of drug may impact favorability.• It is not possible to develop an IVIVC for everyproduct and are generally considered impractical inGeneric Industry, though IVIVR may have limitedutility in development.• The decision to pursue an IVIVC should remain thechoice of the company to which the product belongs.It should not be forced upon development, asprobability of success may be questionable in manycases.

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