Monday, May 5, 2008

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.

Sunday, May 4, 2008

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?