First in Human Dose Calculation

The other day, I got an opportunity to teach students of MS in Drug Development course about procedures used in calculating first human dose for Phase I clinical trials. I started out explaining the objectives of Phase I studies, various study designs and the need to estimate safe starting doses. The process outlined in the FDA guidance document for estimating the MRSD (Maximum Recommended Starting Dose) is based on doses administerd to different animal species, observed toxicities and a proposed algorithm (as mentioned below) . Additional methods reported include PK guided approach based on AUC and clearance. You can find my slides here.

Let me know your thoughts on these methods. All comments, suggestions, criticism will be highly appreciated.

PK Model (NONMEM)

I have been working on a drug administerd orally to paediatric patient and follows a one compartmental model. Following is the control stream and the output obtained running the model with NONMEM VI. The estimates obtained do match the reported literature values. My next plan is to use the estimates obtained to model the PD data.

$PROB RUN# 100

$INPUT C ID TIME DV AMT DOSE MDV WT

$DATA 100.CSV IGNORE=C

$SUBROUTINES ADVAN2 TRANS2

$PK

TVCL=THETA(1)*(WT/70)**0.75

CL=TVCL*EXP(ETA(1))

TVV=THETA(2)*(WT/70)**1

V=TVV*EXP(ETA(2))

TVKA=THETA(3)

KA=TVKA*EXP(ETA(3))

S2=V
TAD=TIME SID=ID

$ERROR Y = F + F*ERR(1) + ERR(2)

IPRED=F

$EST METHOD=1 PRINT=20 NOABORT MAXEVAL=9999 MSFO=100.msf

$THETA

(0.1, 14) ;[CL/F]

(0.1, 51);[V]

(0.1, 8) ;[KA]

$OMEGA

0.09 ;[P] omega(1,1)

0.04 ;[P] omega(2,2)

0.36 ;[P] omega(3,3)

$SIGMA

0.09 ;[P] sigma(1,1)

0.1 ;[A] sigma(2,2)

$COVARIANCE
$TABLE ID SID TIME DV PRED IPRED CL V KA WT ONEHEADER NOPRINT FILE=100.tab
$$TABLE ID TIME IPRED WRES NOPRINT ONEHEADER FILE=SDTAB100

Output:

CL: 14.14 (37.7%), V:55.2 (20.7%), Ka: 8.12 (130%)

Residual Varaiability: Proportaional (15.4%), Additive (1.03 ug/ml)

Plots of few patients

Any comments/criticism/suggestions to improve the fit?

Learn Vs Confirm

I was reading this interesting and thought provoking article on "LEARNING VS. CONFIRMING IN CLINICAL DRUG DEVELOPMENT" by Lewis Sheiner. The article is available freely on the web here. For those who havent read it, please do so. It may be hard to grasp the details in the first attempt, but if you read it more than once (like I am doing) you will start understanding how one can improve clinical drug development program by implementing the learn- confirm paradigm.

PK/PD Models

All Models Are Wrong,

Some Models Are Useful. George Box

How does one find the useful model? Is the useful model the right one? Since the model keeps on changing with new information, I guess there can never be a right model.

Human Microdosing Studies/ Phase Zero

A Phase Zer0 study involves evaluating pharmacokinetics of a drug after administration of sub-therapeutic or sub pharmacology doses to a small group of healthy volunteers. According to

EMEA position paper, microdose is defined as dose less than 1/100th of the dose calculated to yield a pharmacological effect or a maximum of <= to 100 mcg dose. Using such small doses pharmacokinetic parameters can be estimated using highly sensitive techniques like acceleratoor mass spectrometry (AMS) or positron emission tomography (PET).

Determining pharmacokinetics, pharmacodynamics (binding to target) and metabolism of a drug at such an early stage in humans will help in eliminating compounds that have suboptimal properties and can aid in go or no decision of a compound. This is believed to considerably reduce the cost and time of drug development. US FDA followed with Exploratory IND guidance document in 2006 for conducting such early phase clinical trials. Microdosing or phase 0 studies do not provide any information on safety and efficacy (because of subtherapeutic dose used).

Xceleron has been the forefront in microdosing studies and their site provides some valuable information for anyone interested. National cancer institute had organised a conference on Phase 0 in oncology drug development and am still going through the slides posted here. As such, there have been very few publications on the use of this strategy in drug development. A pubmed search revealed few publications listed below, though none of them are real drug development case studies.

So here is my question for you. Were you (or your company) involved in any mircodosing studies? What is your opinion on the long term use of Phase o studies? Can modeling & simulation play any role in extrapolating data from these studies?


Microdosing Study Publications
1. Clinical Cancer Research 13, 4164-4169, July 15, 2007
2. Clin Pharmacol Ther. 2006 Sep;80(3):203-15
3. Clin Pharmacol Ther. 2006 Sep;80(3):216-27
4. J Clin Pharmacol. 2005 Oct;45(10):1198-205

Do schools kill creativity?

Check out this video...
http://www.ted.com/talks/view/id/66
I bet you would love this.

PKPD Books

I havent had a chance to blog about anything in the past few days. I wanted to break the ice and start writing something today. So, here I go with the list of important books that I have read or am reading and am aiming to finish reading in the next few months. I usually start with the chapters most interesting and try to read a chapter a day. So here is my list...

1. Pharmacokinetic-Pharmacodynamics Modeling and Simulation -Peter L Bonate. I have already finished most chapters and feel its a very good book for beginners, loaded with all the essential basics, and boosting inspirational quotes at the start of each chapter.

2. Pharmacometrics: The Science of Quantitative Pharmacology - Ene I. Ette and Paul J. Williams. I have read the book and have used some of the NONMEM codes for parent metabolite, eneterohepatic recirculation and PKPD modeling. Excellent book and a must read for those aspiring to be a pharmacometrician.

3. Principles of Clinical Pharmacology. Arthur J. Atkinson et al. A very good book covering all aspects of clinical pharmacology with chapters on clinical pharmacogenetics, population pharmacokinetics, disease progression models, drug therapy in pregnant and nursing women, drug discovery and development... Very ineteresting range of topics and a must read.

4. Dose Optimization in Drug Development - Rajesh Krishna. As the title goes, this book provides views of various experts on dose selection and optimization in drug development. It covers important topics like disease progression modeling, dose selection in first in man studies, biomarkers, PK/PD variability, pharmacogenetics, paediatric dose optimization
As quoted by Rajesk Krishna " The book will appeal to anyone who would like to appreciate how integration of sciences facilitates meaningful changes in delineating risk versus benefit and ultimately in the selection of safe and effective doses"


How about you? I would appreciate if you could share some of the books that you have enjoyed learning.

Sex and/or Gender

I was surprised to know that gender and sex have different meanings. During a presentation at Cincinnati Childrens Hospital, Dr. Nick Holford had asked us to explain the differences between sex and gender. There was a moment of silence amongst the students contemplating on the issue. It seems that the scientific community has been using the terms interchangeably. Sex based differences in pharmacokinetics of drugs have been investigated and there is a fair amount of literature suggesting men and women absorb, distribute and metabolise some drugs differently.


Women have been found to have higher gastric PH, slower gastric emptying rate, higher percentage of fat leading to higher volume of distribution, higher rates of metabolism for CYP3A4 substrates and higher rates of clearance for P-gp substrates. In addition, fluctuation in homonal levels have also been implicated for differences in CYP3A4 activity. However, there is a relative paucity of data on sex differences in pharmacodynamics of drugs. Perhaps the most dramatic example is women developing torsades de pointes (a type of ventricular arrythmia) after taking ceratin medications. Women treated with anti-HIV drugs, especially protease inhibtors have also had higher incidences of adverse effects in several studies. They also experienced greater efficacy rates when compared to men, emphasising the need of more prospective studies to identify the mechanisms behind these observations.

As the participation and inclusion of women in clinical trials increases, we will be able to understand the significance of these differences. Going back to the differences in the terminology of SEX and GENDER, Kim & Nafziger in their commentary (reference 1) state that gender and sex are distinct concepts. Sex differences between men and women are attributed to biologocal differences including genetic, hormonal, reproductive and physical differences. While, gender difference are attributed to behavioral and cultural aspects like smoking, alcohol consumption etc. More interesting points on the differences with examples at WHO site

Feel free to comment and correct!

References:
1. Is it sex or is it gender? Clin Pharmacol Ther 2000;68:1-3.
2. Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol. 2004;44:499-523.
3. The influence of sex on pharmacokinetics. Clin Pharmacokinet. 2003;42(2):107-21

I'm Blogging

I have initiated this blog to enhance my understanding, and stimulate discussions on PK/PD principles & their use in drug development process . I would like to jump start my discussions by picking up some important manuscripts. Please feel free to comment, criticise and offer suggestions.