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On Modeling Methods and Predictability of  In-Vitro-In-Vivo Correlation (IVIVC)   of Oral Controlled Release ProductsPrese...
Outline•   Relevance and definition of IVIVC•   Biopharmaceutics classification system (BCS)•   Levels of IVIVC•   Generat...
Dissolution in CR Formulation Development          For Market                           Retig et al. Diss Tech, Feb. 2008,...
Definition of IVIVC• In-vitro-in-vivo correlations (IVIVC) are the  predictive, mathematical models relating an in vitro  ...
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    %dru...
Overall Approach                                                                         IVIVC                            ...
Generation of In-Vitro Release Profile• USP apparatus 1 (basket, 100 rpm) or 2  (paddle, 50&75 rpm)• Aqueous dissolution m...
Dissolution Specifications• Without IVIVC   – ± 10% of the label claim from mean dissolution profile of the bio or     cli...
Mean Doxazocin Concentrations from     CR Formulations; n = 24                8mg fed SD                     8mg fasted SD...
Oral CR of Diltiazem with a Clinically Proven           IR (first market entry)                                           ...
Limits to Oral Drug Absorption   Rate-limiting             Conditions                     Comments      StepsDissolution l...
Generation of In-Vivo Release Profile• Compartmental Models  – Wagner-Nelson  – Loo-Riegelman• Linear Systems Models  – De...
Wagner Nelson (1 compartment)
Loo-Riegelman (2 Compartments)
ConvolutionWhere,C(t) = Plasma drug concentrations after oral doseCδ(t) = Plasma concentrations after an IV dose or a dose...
Deconvolution
Other Methods of Generating             In-Vivo Release Profiles• Macroscopic Mass Balance•    Where An is absorption numb...
Systemic Drug Absorption:Carbamazepine CR 15N Stable Isotope Study                      Wilding et al. Br J Clin Pharmac (...
Systemic Drug Absorption:CarbamazepineCR 15N Stable Isotope Study                 Wilding et al. Br J Clin Pharmac (1991),...
IVIVC Model Predictability• PE% Cmax             Cmax (pred) – Cmax (obs)                         Cmax (obs)• PE% AUC     ...
IVIVC Model Predictability(Weak acid; highly lipophilic; bioavailability 60-70%)                  Lobenberg R. www.aapspha...
IVIVC Bench Issues• Reliable and biorelevant dissolution method and apparatus  suitability   – Qualification and calibrati...
IVIVC Modeling Issues• Intra- and Inter-subject variation   – High variations can distort the mean data and in turn the   ...
Conclusions•   Biorelevant and reliable dissolution profiles can predict the in-vivo    absorption of drugs from CR formul...
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In vitro-in-vivo correlation

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Transcript of "In vitro-in-vivo correlation"

  1. 1. 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
  2. 2. 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
  3. 3. Dissolution in CR Formulation Development For Market Retig et al. Diss Tech, Feb. 2008, 6-8
  4. 4. 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
  5. 5. Biopharmaceutics Classification System (BCS) Amidon et al. (1995), Pharm Res, 12, 413-420
  6. 6. • 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.
  7. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. 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.
  11. 11. 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.
  12. 12. 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))
  13. 13. Generation of In-Vivo Release Profile• Compartmental Models – Wagner-Nelson – Loo-Riegelman• Linear Systems Models – Deconvolution – Convolution• Mathematically they all yield the same result
  14. 14. Wagner Nelson (1 compartment)
  15. 15. Loo-Riegelman (2 Compartments)
  16. 16. 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
  17. 17. Deconvolution
  18. 18. 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
  19. 19. Systemic Drug Absorption:Carbamazepine CR 15N Stable Isotope Study Wilding et al. Br J Clin Pharmac (1991), 32, 573-579
  20. 20. Systemic Drug Absorption:CarbamazepineCR 15N Stable Isotope Study Wilding et al. Br J Clin Pharmac (1991), 32, 573-579
  21. 21. IVIVC Model Predictability• PE% Cmax Cmax (pred) – Cmax (obs) Cmax (obs)• PE% AUC AUCmax (pred) – AUCmax (obs) AUCmax (obs)
  22. 22. IVIVC Model Predictability(Weak acid; highly lipophilic; bioavailability 60-70%) Lobenberg R. www.aapspharmaceutica.com/meetings/files/126/lobenberg.pdf
  23. 23. 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
  24. 24. 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
  25. 25. 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
  26. 26. Thank you very much
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