On Modeling Methods and Predictability of In-Vitro-In-Vivo Correlation (IVIVC) of Oral Controlled Release ProductsPresented at BIOBIO 2010, Hyderabad, India, March 1-3, 2010 Dr. Bhaswat S. Chakraborty Sr. Vice President, R&D, Cadila Pharmaceuticals
Outline• Relevance and definition of IVIVC• Biopharmaceutics classification system (BCS)• Levels of IVIVC• Generation of in-vitro release profile• In-vivo PK profile• Generation of in-vivo release profile – Compartmental – Linear Systems – Other Methods• Predictability Error• Issues• Conclusion
Dissolution in CR Formulation Development For Market Retig et al. Diss Tech, Feb. 2008, 6-8
Definition of IVIVC• In-vitro-in-vivo correlations (IVIVC) are the predictive, mathematical models relating an in vitro property such as dissolution and an in vivo response, e.g., amount of drug absorbed, thus allowing an evaluation of the QC specifications, change in process, site, formulation and application for a biowaiver etc.• Valid in vitro and in vivo methods valid IVIVC
Biopharmaceutics Classification System (BCS) Amidon et al. (1995), Pharm Res, 12, 413-420
• Level A – point-point; first Levels of IVIVC deconvolution to get in vivo %drug absorbed, then Level B compare with %dissolved• Level B – Statistical moments; MRT or MDT in vivo vs. MDT in vitro• Level C – single point; PK parameter vs. %dissolved Level AC Level Level A Malinowski and Marroum, Encyclopedia of Contr. Drug Deliv.
Overall Approach IVIVC Scale factor API –1 Physicochemi- BCS Class PK Data IVIVR cal Properties2 Dosage Form Biorelevent Properties Dissolution3 Computer Modeling Using Convolution including Transporters, PK Models, and PK Parameters, API properties or Drug Release Data Wang et al (2009) Diss Tech, 8, 6-12
Generation of In-Vitro Release Profile• USP apparatus 1 (basket, 100 rpm) or 2 (paddle, 50&75 rpm)• Aqueous dissolution medium, 900 ml – pH 1-1.5, 4-4.5, 6-6.5 & 7-7.5 at 370C – A surfactant may be required• In-vitro food effect – Rotating dialysis cell method – Effects of oils, enzymes and pH
Dissolution Specifications• Without IVIVC – ± 10% of the label claim from mean dissolution profile of the bio or clinical batch – Can be >10% but range not >25% in certain cases• With IVIVC – All batches should have dissolution profiles with upper and lower predicted bioequivalence• Proper or Biorelevant Dissolution conditions – Consider medium, volume, duration, apparatus (hydrodynamics) – pH 1 – 7.4 – Predictive of bioavailability • Similar conditions, similar dissolution and similar bioavailability
Mean Doxazocin Concentrations from CR Formulations; n = 24 8mg fed SD 8mg fasted SD 2mg fasted SD Chung et al. Br J Clin Pharmacol. (1999) 48, 678–687.
Oral CR of Diltiazem with a Clinically Proven IR (first market entry) Steady State Single Dose Fasting Malinowski and Marroum, Encyclopedia of Contr. Drug Deliv.
Limits to Oral Drug Absorption Rate-limiting Conditions Comments StepsDissolution limiting Tdiss > 199 min The absolute amount of absorbed drug increases with Peff > 2 × 10-4 cm/sec the increased dose. Dabs >> DosePermeability Tdiss < 50 min The absolute amount oflimiting absorbed drug increases with Peff < 2 × 10-4 cm/sec the increased dose. Dabs >> DoseSolubility Tdiss < 50 min The absolute amount oflimiting absorbed drug does not Peff > 2 × 10-4 cm/sec increase with the increased Dabs < Dose dose. (Yu, Pharm. Res. 16:1884-1888 (1999))
Generation of In-Vivo Release Profile• Compartmental Models – Wagner-Nelson – Loo-Riegelman• Linear Systems Models – Deconvolution – Convolution• Mathematically they all yield the same result
ConvolutionWhere,C(t) = Plasma drug concentrations after oral doseCδ(t) = Plasma concentrations after an IV dose or a dose of oral solutionUpon taking the derivative of C(t) wrt time: When Cδ(0) = 0
Other Methods of Generating In-Vivo Release Profiles• Macroscopic Mass Balance• Where An is absorption number and Cb* is the lumen drug concentration • Inverse Gaussian Where MIT is mean input time and CV2I is a normalized variance
Systemic Drug Absorption:Carbamazepine CR 15N Stable Isotope Study Wilding et al. Br J Clin Pharmac (1991), 32, 573-579
Systemic Drug Absorption:CarbamazepineCR 15N Stable Isotope Study Wilding et al. Br J Clin Pharmac (1991), 32, 573-579
IVIVC Model Predictability(Weak acid; highly lipophilic; bioavailability 60-70%) Lobenberg R. www.aapspharmaceutica.com/meetings/files/126/lobenberg.pdf
IVIVC Bench Issues• Reliable and biorelevant dissolution method and apparatus suitability – Qualification and calibration of equipment, sink conditions – Ability to discriminate non-BE lots – Apparatus and media for continuous IVIVC (minimum 3 lots) and tuning with gi conditions• Accurate deconvolution of the plasma concentration-time profile – e.g., %absorbed in-vivo may be reflective of processes other than release; absorption rate limitation is common for CR products• Dissolution Specifications – Based on biological findings rather than pharmacopeial or mechanistic
IVIVC Modeling Issues• Intra- and Inter-subject variation – High variations can distort the mean data and in turn the deconvolution – Enterohepatic recycling or second peak – Reproducibility of reference profiles• Modeling – Smoothness of input and response functions – Stability of numerical methods – Jumps in input rate functions, e.g., delayed release or gastric emptying – Statistical properties of the models
Conclusions• Biorelevant and reliable dissolution profiles can predict the in-vivo absorption of drugs from CR formulations• Batches with similar dissolution will be BE and dissimilar dissolution will be non-BE• Several methods exist for estimating in-vivo absorption – Mainly mass balance (compartmental) and superposition (convolution)• Level A (point-to-point) or B (mean dissolution times) correlation can be obtained for BCS class 1 or 2 drugs• At least 3 lots (desirable, fast and slow) must be established with IVIVC and proper reference• IVIVC is useful in – QBD, SUPAC and biowaivers…• Both practical and modeling issues must be addressed