Good Modeling

Here is something to think about...

From a mathematical point of view, the art of good modeling relies on: (i) a sound understanding and appreciation of the biological problem; (ii) a realistic mathematical representation of the important biological phenomena; (iii) finding useful solutions, preferably quantitative; and most crucially important, (iv) a biological interpretation of the mathematical results in terms of insights and predictions. The mathematics is dictated by the biology and not vice versa. Sometimes the mathematics can be very simple. Useful mathematical biology research is not judged by mathematical standards but by different and no less demanding ones.

- Jim Murray, 1993

Hepatotoxicity in Drug Development

Liver toxicity has been one of the most common reasons for drug withdrawal in the past e.g Benoxaprofen (Oraflex), ticrynafen (Selacryn), bromfenac (Duract) and troglitizone (Rezulin). It has lead to black box warning for drugs like rifampicin, acetaminophen, valproic acid etc, due to their potential to cause liver injury. In some cases, drugs have not been approved because of its hepatotoxicity. Acetaminophen is a classic example where drug induced liver injury (DILI) is observed due to overdosage. The mechanism involves formation of a highly reactive metabolite N-Acetyl-p-benzoquinoneimine, by cytochrome P450 enzymes (CYPs) CYP2E1, CYP1A2, and CYP3A4. Accumulation of this metabolite results in cell death and hepatocellular necrosis. Patients with acetaminophen hepatotoxicity are treated with N-acetylcysteine, but still approximately 500 patients die each year.

In the course of drug discovery and development, why is it difficult to determine the potential of a new chemical entity to cause hepatotoxicity or DILI? Though every compound undergoes rigorous testing in animal models and in vitro hepatocytes, most of the compounds pass through without being identified as hepatotoxic, probably due to lack of an appropriate model or due to differences in absorption, distribution, metabolism, elimination (ADME) between humans & animals. Other reasons include age, sex, genetic polymorphisms, disease conditions, drug -food and drug-drug interactions (CYP Induction/Inhibition). All these factors decrease the predictive power of non-clinical studies.

An increase in levels of the liver enzymes like alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin are signs of liver toxicity. Evaluation of these enzymes are routinely performed in clinical trials to assess drug induced liver injury. According to FDA guidance document, Hy’s Law (Hy Zimmerman) in determining DILI cases have the following three components:

“1. The drug causes hepatocellular injury, generally shown by more frequent 3-fold or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control agent or placebo.
2. Among subjects showing such aminotransferase (AT) elevations, often with ATs much greater than 3xULN, some subjects also show elevation of serum TBL to >2xULN, without initial findings of cholestasis (serum alkaline phosphatase (ALP) activity >2xULN).
3. No other reason can be found to explain the combination of increased AT and TBL, such as viral hepatitis A, B, or C, preexisting or acute liver disease, or another drug capable of causing the observed injury.”

If a patient has found to have AT 3xULN or TBL is greater than 2xULN, the tests need to be repeated within 48-72 hours to confirm the abnormalities.

A recent example of hepatotoxicity observed in a new drug and the response of FDA has been cited in a white paper formulated for the workshop “Assessing and Accelerating Development of Biomarkers for Drug Safety” as follows

“A major pharmaceutical company submitted an NDA application for treatment of a chronic disease. The FDA agreed with the sponsor’s efficacy data. However, it was noted that among ~4,000 treated patients in clinical trials, two developed elevations in both serum alanine aminotransferase and bilirubin. As a prerequisite for approval, the company was told to conduct a new safety study of 10,000 patients treated with drug for one year, and to also include an additional 10,000 subjects receiving comparator treatment for one year. This news will cost the company >$200M to conduct the trial, ~3 years off patent, and loss of market entry position in class.”

This clearly shows how important it is to determine the toxicity to liver during the phases of drug development. I guess this post will stimulate some fruitful discussions and ideas related to DILI.

Other Guidances/References: EMEA -Non-Clinical Guideline On Drug-Induced Hepatotoxicity[PDF], FDA White Paper on Nonclinical Assessment of Potential Hepatotoxicity in Man [PDF]

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A=X+Y+Z: Sucess Formula

Good Morning!

Here is something simple to think about-

"If A equal success, then the formula is A equals X plus Y and Z, with X being work, Y play, and Z keeping your mouth shut - Albert Einstein

Wish you "A" in your day!

MWSUG - Midwest SAS User Group Scholar

I was fortunate enough to be selected as a student scholar in the recent midwest SAS user group conference held at Mariott Hotel, Indianapolis. This scholarship included a free registration and accomodation during the conference. It was a unique opportunity to mingle with SAS/JMP users from industry & academia and lean from the experts. The presentations were in the following categories

Application Development
Data Visualization
Pharmaceutical Applications
SAS Presents
Statistics and Data Analysis
Tutorials
JMP

Being a midwest user's conference, I think MWSUG 2008 had around 400-500 attendees and was a small one when compared to AAPS with approximately 10,000 attendees. Dr. John Sall, Co-founder and Executive Vice President of SAS Institute and leader of the JMP business division was the key note speaker. He talked about the journey of JMP since late 1980s to the current version of JMP7.0. I especially enjoyed the talk on Mixed Effect Models and Bayesian analysis using SAS. I am not a SAS/JMP expert, but am comfortable using them for some of the statistical analysis.

In addition to the various presentations and hands on SAS workshop, MWSUG included a Las Vegas Casino Night with games like Craps, Blackjack, Roulette, 3-Card Poker, Money Wheel and Texas Hold’em Poker area. Each of us received a $500 fake money to play the games. This was the second time I was ever gambling in my life (can you believe that?) and in a Mariott turned Las Vegas Casino. The first time was when I visited Las Vegas and was trying my hand at the slot machines. Anyways, I did have fun on the casino night.

Did you have an experience similar to this? I would be happy to hear and learn from you!

Population Pharmacokinetics/Pharmacodynamics

Population pharmacokinetics (PopPk) is the study of variability in plasma concentrations between and within individuals. It helps in identifying the demographic, pathophysiological, environmental and drug related factors that contribute to the variability observed in safety and efficacy of a drug. Unlike traditional PK studies where healthy volunteers are subjected to intensive sampling to determine PK parameters, PopPk studies offer an advantage of estimating PK parameters in target patient population with sparse sampling methodology. PopPK uses a nonlinear mixed effects modeling (NONMEM) approach. Variability in NONMEM is characterized in terms of fixed and random effects. The fixed effects are population average values of pharmacokinetic parameters such as clearance & volume of distribution, that may in turn be a function of patient characteristics. The random effects quantify the variability that is not explained by the fixed effects. These random effects include inter-subject, intra-subject, inter-occasion and residual variability. This methodology has also been extended to model population pharmacokinetic/pharmacodynamics (Pop PK/PD) relationships. This NONMEM approach was introduced by Lewis Sheiner and Stuart Beal approximately 30 years back. It has now become an integral part of drug development in industries and FDA review process.

Some of the softwares that have been used for modeling are as follows
NONMEM (most widely used)
ADAPT
Monolix
NPEM
NPAG (USC*PACK)
WinNonmix
Kinetica
SAS (PROC NLMIXED)
Splus

Pop PK/PD has led to a new discipline known as pharmacometrics. Barrett et al in J Clin Pharmacol 2008;48:632-649 define “Pharmacometrics” as that branch of science concerned with mathematical models of biology, pharmacology, disease, and physiology used to describe and quantify interactions between xenobiotics and patients, including beneficial effects and side effects resultant from such interfaces. So if you are a pharmacist, pharmacologist, statistician or biomedical engineer with good understanding of pharmacokinetics, pharmacodynamics, biological sciences, statistical and computational tools, you have a good chance to become a pharmacometrician. They are paid well both in the industry and the FDA. Infact, FDA has its own pharmacometrics group headed by Joga Gobburu and are promoting the use of modeling & simulation in drug development.

Are you a pharmacometrician or a PK/PD scientist? Is there a specific software that you use to model the data?

Bioavailability/Bioequivalence Guidelines

Sometimes its hard to find regulatory guidance documents on the web. One has to scroll through several pages before you actually find what you need. To make things easier, I previously had a webpage where the Bioavailability/Bioequivalence (BA/BE) guidances of various countries were put together under one page. Now, I will be posting the guidance documents on various topics on this blog. Today, I will start with BA/BE and cover as many topics in clincal pharmacology as possible in the future. If you are working in the generics industry and happen to do clinical studies supporting the ANDA (Abbreviated New Drug Application), you may want to bookmark this page and become familiar with following documents.

Note: All links have been updated (March 2014).

US FDA 

1. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations (Issued 3/2003, Posted 3/19/2003)[PDF]
 NEW DRAFT FOR COMMENTS: Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs- General Considerations (Issued 3/2014)[PDF]

2.  Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application- Draft (12/2013) [PDF]
3. Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (Posted 4/2/2003)[PDF]
4. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (Issued 8/2000, Posted 8/31/2000) [PDF]
5. Food-Effect Bioavailability and Fed Bioequivalence Studies (Issued 12/2002, Posted 1/30/2003) [PDF]
6. Handling and Retention of BA and BE Testing Samples (5/25/2004) [PDF]
7. Statistical Approaches to Establishing Bioequivalence (Issued 2/2001, Posted 2/1/2001)[PDF]
8. Submission of Summary Bioequivalence Data for ANDAs (04/2009) [PDF]
9. Bioequivalence Recommendations for Specific Products (06/2010) [PDF]
10. Bioanalytical Method Validation (05/2001)[PDF]. This guidance is under revision  and the draft version dated 09/2013 has been distributed for comments.(09/2013)[PDF]
11. Dissolution Methods Database 

EMA

1. Guideline on the Investigation of Bioequivalence (08/2010)[PDF]

2.  Appendix IV of the guideline on the investigation on bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1): Presentation of biopharmaceutical and bioanalytical data in module 2.7.1 (06/2012) [PDF]
3. Questions & Answers:Positions on specific questions addressed to the pharmacokinetics working party (10/2013) [PDF]
4. Bioanalytical Method Validation (02/2012) [PDF]
5. Modified-release oral and transdermal dosage forms: Section II (01/2000) [PDF]
6. Pharmacokinetic and clinical evaluation of modified-release dosage forms- draft (2013)[PDF]

CANADA (HPMB)

Bioavailability and Bioequivalence [html]

AUSTRALIA (TGA)
Guidance on the Investigation of Bioequivalence [PDF].
TGA has adopted the EMA guidance document with the note "While this guidance suggests that the design and conduct of the study should follow EU regulations on Good Clinical Practice, sponsors should note that the EU Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) has been adopted in Australia with TGA annotations.

JAPAN [PMDA]
There is no official english version of the guidance document, but the presentation on "Approval Review of Generic Drugs in Japan" available here and here by the reviewers from the Office of Generic Drugs, PMDA may be beneficial.

INDIA [CDSCO]
Draft Guidelines for Bioavailability/Bioequivalence Studies on Conventional and Extended Release Dosage Forms

BEBAC- Helmut Schütz also maintains a comprehensive list of BABE guidelines for almost all the countries and you can find it here.

Let me know if I am missing something!

A cup of Tea

One of my favorite Zen story - A cup of Tea

Nan-in, a Japanese master during the Meiji era (1868-1912), received a university professor who came to inquire about Zen.

Nan-in served tea. He poured his visitor's cup full, and then kept on pouring.

The professor watched the overflow until he no longer could restrain himself. "It is overfull. No more will go in!"

"Like this cup," Nan-in said, "you are full of your own opinions and speculations. How can I show you Zen unless you first empty your cup?"

What do you think?