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The literature has many examples where the pharmacokinetics in males is
different than the pharmacokinetics in females.
Is anyone aware of any examples where these differences have actually
made it into the product label such that males are advised to get a
different dose than females?
Thanks in advance,
Peter L. Bonate, PhD, FCP
Director, Pharmacokinetics
Genzyme Oncology
4545 Horizon Hill Blvd
San Antonio, TX
78229
phone: 210-949-8662
fax: 210-949-8219
email: peter.bonate.at.genzyme.com
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Peter:
I have been reviewing product labels from drugs approved since 2000. I
am
not aware of any differences in dosage recommended on any label since
then.
Obviously there are some labels such as antiandrogens that warn against
exposure in women but that is because of pharmacodynamic issues not
metabolism.
Carol Collins MD
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It has been known for several years that men and women metabolize drugs
at different rates. Hormonal influences in women, as well as
physiological differences, including higher fat content, lower body
weight, different blood flow regulation to organs and smaller organ
size could all play a role in the pharmacological response to any given
drug. This is the reason why those involved with clinical studies must
now attempt to include female subjects in clinical research so as to
address these issues.
I believe there are a few drugs that have been withdrawn from the
market or maybe had their labeling information updated to inform of
greater risk of toxicity in females. A classical example is that of the
antiarrhythmic Amiodarone, which has been shown to pose a greater risk
of arrhythmias in females than males.
If you go to the site:
http://www.torsades.org/medical-pros/drug-lists/drug-lists.htm (and
select View List - db), you can see a more comprehensive list of drugs
that have distinct effects in women and men. Those include the
antiarrhytmics I mentioned, but also some antibiotics, antipsychotics,
opiates, etc.
I hope that was helpful to you.
Regards,
Alessandra
Alessandra Milesi-Halle, M.D.
Department of Pharmacology and Toxicology
University of Arkansas for Medical Sciences
4301 West Markham, slot 611
Little Rock, Arkansas 72205
Phone: (501)686-6551
Fax: (501)686-5521
MilesihalleAlessandr.aaa.uams.edu
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There is a very recent article: Anthony M, Journal of Women's Health,
volume 14, number 1, 2005 that specifically discuss the issues of
pharmacodynamics but refers to plenty of other articles with regulatory
perspectives, you might find something there. Good luck.
Jean-Pierre Moreau
DMPK
MDS Pharma Services
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Dear Peter,
Actually, there is at least one drug where patient's gender has been
taken into account in the product label: the anticancer drug
carboplatin.
FDA approved label
(http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?
GN=carboplatin) allows carboplatin dosing according to Calvert's
formula (J Clin Oncol. 1989 Nov;7(11):1748-56), which is actually and
by far the way worldwide oncologists dose it. This formula takes into
account the target AUC of carboplatin and the patient's glomerular
filtration rate (GFR):
Carboplatin dose = (GFR+25) x target AUC
And GFR is routinary calculated with formulas that estimate creatine
clearance, which take gender into account (Ann Intern Med 1999 Mar 16;
130 (6): 461-70)
(http://hcc1.musc.edu/hemonc/carboplatin_dose_calculator.htm).
So, according to carboplatin's label, males and females may be given
different doses (males receive higher doses than females)
Best regards,
Emiliano
Emiliano Calvo, MD, PhD
Institute for Drug Development
Cancer Therapy and Research Center
7979 Wurzbach, Zeller Building, 4th floor, Room #Z414H
San Antonio, Texas 78229
Telephone: (210) 616-5970
Fax: (210) 692-7502
ecalvo.-a-.idd.org
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Alessandra:
I completely agree with you in the necessity of evaluating the
pharmacokinetics of drugs in both men and women. However, the latest
label
for Amiodarone does not discuss specific warnings for women except
during
pregnancy and breast feeding.
Carol Collins MD
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Peter:
If I understand your question, it is are there any product labels that
specifically address gender differences in metabolismz? If that is the
question, the carboplatin label does suggest different dosages for GFR
but
gender is only one of the patient characteristics that may affect GFR
so I
would not consider this a labeling difference specific to gender.
Carol Collins MD
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"Calvo, Emiliano" wrote:
> And GFR is routinary calculated with formulas that estimate creatine
> clearance, which take gender into account (Ann Intern Med 1999 Mar 16;
> 130 (6): 461-70)
> (http://hcc1.musc.edu/hemonc/carboplatin_dose_calculator.htm).
>
> So, according to carboplatin's label, males and females may be given
> different doses (males receive higher doses than females)
>
This response reflects a common misconception. We are not aware of any
differences in renal function between men and women when it has been
looked for (Matthews et al. 2004). Creatinine clearance prediction
formulae such as Cockcroft and Gault use sex (and age and weight) to
predict the production rate of creatinine. Sex reflects the lower
muscle mass/kg in women. Sex is a body composition predictor and does
not mean that renal function differs in men and women.
Note that we use renal function to predict a size independent quantity.
We would expect, on
average, that renal clearance (and non-renal clearance) is bigger in
men than women because of differences in size. Once size has been
accounted for then one can start looking for sex differences.
The review by Cummins et al. (2002) has demonstrated that there are
small and clinically irrelevant sex differences in CYP3A4 clearance.
This finding is supported by the review of Cotreau et al. (2005) who
addressed the effects of sex on CYP activity and concluded that for
most drugs sex-related differences in clearance were negligible when
clearance was expressed as a function of size.
Put on weight - forget sex!
Nick, Carl and Steve
Coutreau MM, von Moltke LL, Greenblatt DJ. The influence of age and sex
on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet
2005;44:33-60.
Cummins CL, Wu CY, Benet LZ. Sex-related differences in the clearance
of cytochrome P450 3A4 substrates may be caused by P-glycoprotein. Clin
Pharmacol Ther 2002;72(5):474-89
Matthews I, Kirkpatrick C, Holford NHG. Quantitative justification for
target concentration intervention - Parameter variability and
predictive performance using population pharmacokinetic models for
aminoglycosides. British Journal of Clinical Pharmacology
2004;58(1):8-19
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology University of
Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
Stephen Duffull, Carl Kirkpatrick
School of Pharmacy, University of Queensland
Brisbane 4072, Australia
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We have been working since 5 years ago with both populations and alter
neaqr
of 70 BE studies we found only two cases in which there is a clear
gender
difference, not related to hormonal status or BMI these are fluoxetine
and
fluconazol, at least here in Mexico there is no a single label
addressing for
gender differences
Greetings
Fermin Valenzuela MD
Director
Center for Clinical Pharmacology and Biopharmaceutical Research
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Matthews et al are incorrect. There are apparently differences in
renal secretory function demonstrated both by apparent affinity and by
ability to inhibit at least organic cation transport.
Amantadine is a great example, where renal tubular secretion is
about 40% lower in women, and the sex difference can be eliminated by
ingestion of concurrent doses of quinine and quinidine. This finding
has
implications for dosing of this drug as a prophylactic intervention
against
influenza A in nursing home settings, and fits with the observations in
the
literature that most toxicity to this drug in the elderly is reported in
females. However, this finding has not resulted in any mandated
changes to
the product monograph.
As well, there is preliminary evidence that loracarbef renal tubular
secretion is also considerably less in women than in men. However, due
to
the high concentrations in the urine, this finding is not likely to be
clinically important, especially in the case of UTIs.
Dan Sitar
Dr. Daniel Sitar
Professor and Head, Pharmacology and Therapeutics
Professor, Internal Medicine (Clinical Pharmacology)
Tel: 204-789-3532 FAX: 204-789-3932
Email: sitar.-at-.cc.umanitoba.ca
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Daniel Sitar wrote:
> Matthews et al are incorrect. There are apparently differences in
> renal secretory function demonstrated both by apparent affinity and by
> ability to inhibit at least organic cation transport.
>
We do not agree that Matthews et al are incorrect. That study
demonstrated no
difference in size adjusted renal function between men and women based
on models for
gentamicin clearance -- a drug thought to be eliminated renally
primarily by
filtration without secretion.
We are certainly happy to qualify our previous posting on this topic to
say that there
is no evidence for differences in renal filtration function between men
and women.
Daniel Sitar wrote:
> Amantadine is a great example, where renal tubular secretion is
> about 40% lower in women, and the sex difference can be eliminated by
> ingestion of concurrent doses of quinine and quinidine.
The primary purpose of our contribution to this thread was to emphasize
the need to
account for body size before drawing conclusions about sex differences
in
pharmacokinetic parameters. It would be helpful if you would describe
if the 40% lower
secretion estimate took into account differences in body size. We would
also be
interested in a reference to the literature sources for these
statements.
Nick, Carl and Steve
Matthews I, Kirkpatrick C, Holford NHG. Quantitative justification for
target
concentration intervention - Parameter variability and predictive
performance using
population pharmacokinetic models for aminoglycosides. British Journal
of Clinical
Pharmacology 2004;58(1):8-19
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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Pete:
At the time we published a review on the potential relevance of
sex/gender-related differences in pharmacokinetics a few years ago
(Clin.
Pharmacokinet. 2002, 41(5)), we did not find any dosing recommendations
for
drugs approved in the U.S. that recommend different dosing for men and
women
based on pharmacokinetic differences.
An example where sex-related differences in pharmacokinetics between
males
and females may potentially be at least partially the cause for
different
dosing recommendations may be alosetron:
Alosetron is only approved for the treatment of severe
diarrhea-predominant
irritable bowel syndrome in women. Alosetron did not show clinical
efficacy
in men with severe diarrhea-predominant irritable bowel syndrome. Plasma
concentrations tend to be 30-50% higher in females compared to males.
AUCiv
was 45% higher, AUCoral 87% higher, and Cmax 86% higher in elderly women
compared to men (66-75 yrs) (based on the publicly available FDA review
documents).
Lack of efficacy in males, even at higher concentrations, however, was
interpreted as being suggestive for additional sex-based pharmacodynamic
differences that are not explained by sex-related differences in
alosetron
concentration. Perhaps someone at GSK (the makers of alosetron) reading
this
discussion may shed some light in this issue.
Best regards,
Bernd
Bernd Meibohm, Ph.D., F.C.P.
Associate Professor of Pharmaceutical Sciences
College of Pharmacy
University of Tennessee
874 Union Avenue, Rm. 5p
Memphis, TN 38163, U.S.A.
Phone (901) 448-1206
Fax (901) 448-6940
Email bmeibohm.at.utmem.edu
meibohm.at.attglobal.net
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Hi Bernd:
About alosetron, recently has been published next paper:
A dose-ranging, phase II study of the efficacy and safety of alosetron
in men with
diarrhea-predominant IBS.Am J Gastroenterol. 2005
Jan;100(1):115-23.Chang L,
Ameen VZ, Dukes GE, McSorley DJ, Carter EG, Mayer EA.
Here you can read that alosetron could be also effective in men,
although even is not a
FDA labeled indication (for men).
I think that, perhaps, is not a good example.
Paulo A. Caceres Guido
Unidad de Farmacocinetica Clinica
Hospital de Pediatria Prof. Dr. Juan P. Garrahan
Combate de los Pozos 1881 (CP:1245)
Buenos AIres, Argentina.
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Bernd,
Bernd Meibohm wrote:
> Alosetron did not show clinical efficacy in men with severe
diarrhea-predominant irritable
> bowel syndrome. Plasma concentrations tend to be 30-50% higher in
females compared
> to males. AUCiv was 45% higher, AUCoral 87% higher, and Cmax 86%
higher in elderly women
> compared to men (66-75 yrs) (based on the publicly available FDA
review documents).
Can you say if these sex associate differences take into account
differences in body size? Would you mind giving a more precise
reference to the FDA review documents?
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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Bernd Meibohm asked whether for Alosetron differences in
pharmacokinetics
between the sexes might account for a lack of efficacy in males with
the IBS
while it was found to be active in females. The smaller body weight in
females that has already featured in this correspondence would
presumably be
one explanatory factor, but there are many others.
Wide variances in efficacy data are typical of trials in the IBS so it
is
more likely that efficacy could not be demonstrated to statistically
acceptable levels of probability in the males. Female IBS patients
outnumber
males by about 2- 1 so they were probably enrolled in larger numbers
which
would have overcome this problem. Other possible causes include
behavioural
differences, such as females may follow a more stable life pattern so
symptoms are less variable. They may produce more consistent diary data
because they keep better symptom diaries than males.
It is interesting that Kaitlin and Cairns (2003) reported in the Drug
Information Journal of the DIA (Vol 37, p357-371) that the median times
taken for FDA approvals in 1999-2001 were longest for NCEs aimed at GI
tract
diseases, ie: an astonishing 9.8 years vs 5.9 years for all classes of
drug.
This problem of wide variations in data is apparently the root cause.
Andrew Sutton.
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Alosetron was submitted under PDUFA and had a 6 month review clock.
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Paulo and Andrew:
Thank you for the additional insights into likely explanations for the
suggested differences in diarrhea-predominant IBS in male compared to
female
patients.
Nick:
I completely agree with your earlier statements that it is crucial to
perform body size normalization before meaningful conclusions on sex
differences in pharmacokinetic parameters can be drawn.
The data I was referring to is included in Part 5 of the Clinical
Pharmacology & Biopharmaceutics Review for Lotronex available under
http://www.fda.gov/cder/foi/nda/2000/21107a_Lotronex.htm as well as
Koch et
al., Br J Clin Pharmacol 2002, 53, 238-42.
In table 52 of the FDA document, alosetron clearance after oral
administration is presented in size-normalized form using body surface
area:
Elderly males (age 69.8+/-3.3): 354 +/- 80 mL/min/m2
Elderly females (age 70.3+/-3.4): 269 +/- 72 mL/min/m2
Ronald:
As author of the document I refer to, can you further comment on this
issue ?
Best regards,
Bernd
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One factor in male vs female is body fat. An exaggerated example is
propofol with a more rapid clearance and awakening time for female than
male.
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Bernd,
Thanks for the additional info. Table 52 (and also Table 57) in
http://www.fda.gov/cder/foi/nda/2000/21107a_Lotronex_clinphrmr_P5.pdf
shows small differences in clearance (obained after IV dosing) between
men and women based on the (archaic) method of BSA size normalization.
Group CL mL/min/m2 SD
YoungMen 363.5 83.5
YoungWomen 342.7 139.8
Oldmen 354.1 79.6
OldWomen 269.4 71.5
It seems 12 males and 12 females were studied but I couldnt find out
how many were in each age group. Assuming 6 in each group the
difference in elderly women is statistically significant but the
clinical relevance of a 26% lower CL is unlikely. There is only a 4%
lower clearance in young women compared with young men. The report says
the lower clearance in older women could be because of lower tobacco
use and/or sex hormone effects on 3A4. The latter explanation seems
less likely because I would think that sex hormone differences between
men and women would be more pronounced in younger people.
Overall I would conclude that the existence of a sex associated
difference in clearance for alosetron is unproven because it was only
seen in older women not young women and the association with sex may in
fact be due to other covariates such as age or use of tobacco.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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Vuong,
Vuong Trieu wrote:
>
> One factor in male vs female is body fat. An exaggerated example is
> propofol with a more rapid clearance and awakening time for female
than
> male.
Would you please supply a reference to the original data for this claim?
Do you know if the clearance differences took into account differences
in body size?
Thanks,
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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Hi Nick:
Propofol is something I worked with routinely. Its PK is very
interesting due to rapid absorption into adipose tissue. There are
numerous refs out there as to the male female differences. One that
came to mind is Ward D.S. et al. Anesthesiology (2002) 97: 1401-1408.
Vuong
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Dear Vuong
There may be literature proposing it is male vs female effect, but is
this actually true when body weight is taken into consideration first.
So, I ask you if you could perhaps answer Nicks original question
"Do you know if the clearance differences took into account differences
in body size?"
With kind regards
Carl
School of Pharmacy, University of Queensland, Brisbane, Australia
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Propofol is suitably modeled using three cpt model. The V3, Cl1 and Cl2
exhibited sexual dimorphism whereas Cl1 was only affected by weight. I
think the data are published somewhere by Vuyk Br. J. Anesthesia 86:
183-188. Of course you have to be careful as to which population you
are dealing with- Chinese with lean body mass did not exhibit this
dimorphism (Yu-Hong (2003) Acta Pharmacol Sin 24: 581). Therefore, my
working hypothesis is that of body fat.
I think we been through this thread before!
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> Propofol is something I worked with routinely. Its PK is very
> interesting due to rapid absorption into adipose tissue. There are
> numerous refs out there as to the male female differences. One that
> came to mind is Ward D.S. et al. Anesthesiology (2002) 97: 1401-1408.
>
> Vuong
> ---
I think, that this is probably true, but wouldn't it also be true in
obese
members of either sex? Certainly anecdoteally, the idea that obese
people
have longer recovery times from anesthesia is out there, but is there
evidence? Most anesthetics are rapidly taken up by the tissues. How is
propofil different?
Dale Sharp
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Nick,
For further clarification: the study was performed in 48 individuals
with 12
subjects in each of the four groups (please see the second reference I
provided earlier for details). Thus, the difference in clearance
between
elderly men and elderly women may actually be statistically
significant. I
agree that the lack of a difference between young men and young women
suggests that the observed difference in elderly individuals may not be
causally related to an intrinsic effect of sex (although one might
theoretically think of a sex-age interaction), but rather secondary to
differences in lifestyle or other covariates. Nevertheless, if the
apparent
difference in alosetron clearance between elderly men and elderly women
is
confirmed in larger patient studies, then the same body size-adjusted
alosetron dosing regimen would result in a 32% higher systemic exposure
in
elderly women compared to men, independent of the nature of the
underlying
cause. Whether this is of any clinical relevance with regard to
efficacy or
toxicity, however, is a different question.
In our review in Clin Pharmcokinet in 2002 I referred to in my earlier
posting we concluded to the question about the importance of sex
differences
in pharmacokinetics that most sex-related differences, if at all present
after body size normalization, are relatively rare, generally only
subtle,
and are frequently overlaid by more striking factors determining the
patient's pharmacokinetic phenotype, including genetic and environmental
factors. In addition, their clinical relevance remains unproven.
Coming back to Pete's original question I am not aware of any proven
case in
which sex differences in pharmacokinetics resulted in proven
differences in
therapeutic response warranting different dosing recommendations for
men and
women. Alosetron was the closest example I could think of (based on
initial
efficacy studies only efficacious in women, but not men; potentially at
least partially related to sex differences in pharmacokinetics), but I
guess
our discussions provided insights that even this example is most likely
not
related to intrinsic sex differences in pharmacokinetics.
Thanks for all comments.
Bernd
--
Bernd Meibohm, Ph.D., F.C.P.
Associate Professor of Pharmaceutical Sciences
College of Pharmacy
University of Tennessee
874 Union Avenue, Rm. 5p
Memphis, TN 38163, U.S.A.
Phone (901) 448-1206
Fax (901) 448-6940
Email bmeibohm.-at-.utmem.edu
meibohm.-at-.attglobal.net
--
For more information:
http://cop.utmem.edu/pharmacy/pharmsci/faculty/pharm/bmeibohm/
bmeibohm.html
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Anesthesia agents have different gender differences. Propofol and
midazolam exhibit sexual dimorphism. Thiopental, remifentanil,
sufentanil do not. Of the opioids, only alfentanil exhibited
dimorphism. In that sense propofol is unique.
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Bernd
I still think that there is mileage left in this thread...
> significant. I agree that the lack of a difference between
> young men and young women suggests that the observed
> difference in elderly individuals may not be causally related
> to an intrinsic effect of sex (although one might
> theoretically think of a sex-age interaction), but rather
> secondary to differences in lifestyle or other covariates.
> Nevertheless, if the apparent difference in alosetron
> clearance between elderly men and elderly women is confirmed
> in larger patient studies, then the same body size-adjusted
> alosetron dosing regimen would result in a 32% higher
> systemic exposure in elderly women compared to men,
Thanks for elucidating the data further. There of course remains the
possibility of a sex-age interaction, however you would need to be
certain that other body composition factors had been accounted for
first. It is certain that the proportion of lean to fat mass changes
with age, and it is possible that these changes may differ between males
and females. It would be of use to consider a size metric that accounts
for differences in body composition. So, rather than just normalising
to weight - perhaps it might be useful to normalise to lean body mass.
This may account for the apparent increase in exposure per total body
weight if indeed the proportion of lean mass in elderly women is less
than for men and that lean mass is a better size descriptor for the
functional capacity of the body.
Steve
Stephen Duffull
School of Pharmacy
University of Queensland
Brisbane 4072
Australia
Tel +61 7 3365 8808
Fax +61 7 3365 1688
University Provider Number: 00025B
Email: sduffull.at.pharmacy.uq.edu.au
www: http://www.uq.edu.au/pharmacy/sduffull/duffull.htm
PFIM: http://www.uq.edu.au/pharmacy/sduffull/pfim.htm
MCMC PK example: http://www.uq.edu.au/pharmacy/sduffull/MCMC_eg.htm
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Regarding the discussion on sex differences in alosetron PK around our
paper in Br J Clin Pharmacol, I would like to refer you to a more
recent paper in Alimentary Pharmacology and Therapeutics 2004,
20:223-230 where we further characterized the effects of sex and age,
as well as finding a dependence on BMI (independent of sex), with
correlative evidence that these are related to elimination being
largely mediated by CYP1A2 metabolism. Few drugs are highly dependent
on 1A2 for elimination, which may be fortuitous in that the activity of
this enzyme appears to vary considerably in relation to demographic and
lifestyle factors, including sex, race, BMI, diet (cruciferous
vegetables, broiled meats), smoking, etc.
Kevin M. Koch, PhD
Clinical Pharmacokinetics
Clinical Pharmacology & Discovery Medicine
GlaxoSmithKline
Research Triangle Park, NC 27709
Tel: 919-483-5161 Fax: 919-483-6380
Email: kevin.m.koch.-a-.gsk.com
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