Purpose
To develop a model to explore the dose-response of sildenafil citrate in patients with female sexual arousal disorder (FSAD) based on telephone sexual activity daily diary (TSADD) data obtained in double-blind, placebo controlled clinical studies.
Materials
Data were available on 614 patients with FSAD. A parametric model (Weibull distribution) was developed to describe the probability density function of the time between sexual events. Orgasm satisfaction scores and overall sexual satisfaction scores were simultaneously modeled as ordered categorical variables. Simulations were performed to evaluate the expected clinical response in patients with FSAD.
Results
The expected time between sexual events was approximately 3.5 days. Satisfaction scores increased with time to achieve a plateau after 3 to 4 weeks on treatment. The expected probability of satisfying orgasm (score of 3 and higher) ranged from 34.7% for placebo to 41.6% for 100 mg sildenafil citrate. Treatment effect (difference from placebo) was 6.9% for 100 mg sildenafil citrate, ranging from 0.6 to 24.7% for testosterone levels of 0.1 to 4.0 pg/ml. The treatment effect in postmenopausal women was larger than in premenopausal women.
Conclusion
A modeling and simulation framework to support drug development in FSAD was developed. Sildenafil citrate demonstrated a dose-dependent effect in patients with FSAD.
Similar content being viewed by others
REFERENCES
I. H. Osterloh and A. Riley. Clinical update on sildenafil citrate. Br. J. Clin. Pharmacol. 53:219–223 (2002).
A. M. Traish, N. N. Kim, R. Munarriz, R. Moreland, and I. Goldstein. Biochemical and physiological mechanisms of female genital sexual arousal. Arch. Sex. Behav. 31:393–400 (2002).
F. S. Gragasin, E. D. Michelakis, A. Hogan, R. Moudgil, K. Hashimoto, X. Wu, S. Bonnet, A. Haromy, and S. L. Archer. The neurovascular mechanism of clitoral erection: nitric oxide and cGMP-stimulated activation of BKCa channels. FASEB J. 18:1382–1391 (2004).
E. Laan, R. H. W. van Lunsen, W. Everaerd, A. Riley, E. Scott, and M. Boolell. The enhancement of vaginal vasoconstriction by sildenafil in healthy premenopausal women. J. Women's Health Gend.-Based Med. 11:357–365 (2002).
J. R. Berman, L. A. Berman, H. Lin, E. Flaherty, N. Lahey, and I. Goldstein. Effect of sildenafil on subjective and physiologic parameters of the female sexual response in women with sexual arousal disorder. J. Sex Marital Ther. 27:411–420 (2001).
S. Caruso, G. Intelisano, L. Lupo, and C. Agnello. Premenopausal women affected by sexual arousal disorder treated with sildenafil: a double-blind, cross-over, placebo-controlled study. Br. J. Obstet. Gynaecol. 108:623–628 (2001).
R. Basson, R. McInnes, M. D. Smith, G. Hodgson, and N. Koppiner. Efficacy and safety of sildenafil citrate in women with sexual dysfunction associated with female sexual arousal disorder. J. Women's Health Gend.-Based Med. 11:367–377 (2002).
J. R. Berman, L. A. Berman, S. M. Toler, J. Gill, and S. Haughie. Safety and efficacy of sildenafil citrate for the treatment of female sexual arousal disorder: a double-blind, placebo controlled study. J. Urol. 170:2333–2338 (2003).
S.L. Beal, A.J. Boeckman, L.B, Sheiner. NONMEM User's Guide, Parts I–VII, University of California at San Francisco, San Francisco, 1988–1992.
A. Gelman, X.-L. Meng, and S. Hal. Posterior predictive assessment of model fitness via realized discrepancies. Stat. Sin. 6:733–807 (1996).
Y. Yano, S.L. Beal, and L.B. Sheiner. Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check. J. Pharmacokinet. Pharmacodyn. 28:171–192 (2001).
R. Marin, A. Escrig, P. Abreu, and M. Mas. Androgen-dependent nitric oxide release in rat penis correlates with levels of constitutive nitric oxide synthase isoenzymes. Biol. Reprod. 61:1012–1016 (1999).
FDA: Draft Guidance for industry: female sexual dysfunction: clinical development for products for treatment. http://www.fda.gov/cder/guidance/index.htm. (accessed 02/06/06)
Author information
Authors and Affiliations
Corresponding author
Appendix
Appendix
NONMEM CONTROL STREAMS
Time-to-event model
-
$PROB Weibull time to event
-
$INPUT ID TIME SSAT ORG ORGS AGE RAND TLE MENO DTK
-
STD DLT=DV BSS BOS MDV
-
; TIME DAYS
-
; SSAT satisfaction Score of current SEXUAL EVENT
-
; ORG orgasm 1 yes; 0 no
-
; ORGS orgasm satisfaction score
-
; AGE age in years
-
; RAND Sildenafil dose
-
; MENO menopausal status 0 = pre, 1 = post
-
; TLE testosterone level in ng/ml
-
; DTK pill intake 0 NO, 1 YES
-
; STD study
-
; DLT time since previous sex event
-
; BSS mean sex score at baseline
-
; BOS mean org score at baseline
-
$DATA ... IGNORE=i
-
$PRED
-
DT=DLT
-
IF(DT .EQ. 0) DT=.1
-
LABDA =EXP(THETA(1)+THETA(3)*TIME+THETA(4)*RAND+THETA(7)*DTK+ETA(1))
-
POW=EXP(THETA(2))
-
HAZ=LABDA*POW*(LABDA*DT)**(POW-1)
-
SURV=EXP(–(LABDA*DT)**POW)
-
DENS=SURV*HAZ
-
Y=DENS
-
$THETA
-
...
-
$OMEGA
-
$EST MAXEVALS=3000 PRINT=5 POSTHOC NOABORT METHOD=COND LAPLACE LIKE
-
$COV
Satisfaction score model
-
$PROB satisfaction score model FSAD treatment phase simultaneous fit
-
$INPUT ID TIME DV AGE RAND TLE MENO DTK STD BSS BOS MDV FLAG
-
; TIME days
-
; DV satisfaction Score of current sexual event
-
; AGE age in years
-
; RAND Sildenafil dose
-
; TLE testosterone level in ng/ml
-
; MENO menopausal status 0 = pre, 1 = post
-
; DTK pill intake 0 NO, 1 YES
-
; STD study
-
; BSS mean sex score at baseline
-
; BOS mean org score at baseline
-
; FLAG for DV 1: Orgasm 0: Sexual
-
$DATA ...IGNORE=i
-
$PRED
-
INT1=THETA(1)
-
INT2=THETA(2)
-
INT3=THETA(3)
-
INT4=THETA(4)
-
INT5=THETA(5)
-
FZ=E+THETA(14)*BOS+THETA(13)*AGE+THETA(11)*(1–EXP(–THETA(16)*TIME))
-
PL=THETA(15)*DTK
-
D=(THETA(12)+THETA(20)*MENO)*RAND*DTK*TLE
-
E=FZ+PL+D+EXP(THETA(18))*ETA(1)
-
A1=INT1+E
-
A2=INT2+E
-
A3=INT3+E
-
A4=INT4+E
-
A5=INT5+E
-
; Cumulative probabilities
-
P1=EXP(A1)/(1+EXP(A1))
-
P2=EXP(A2)/(1+EXP(A2))
-
P3=EXP(A3)/(1+EXP(A3))
-
P4=EXP(A4)/(1+EXP(A4))
-
P5=EXP(A5)/(1+EXP(A5))
-
; Probabilities
-
PR0=1–P1
-
PR1=P1–P2
-
PR2=P2–P3
-
PR3=P3–P4
-
PR4=P4–P5
-
PR5=P5
-
;Likelihood
-
IF(FLAG .EQ. 1 .AND. DV .GT. 4.5) Y=PR5
-
IF(FLAG .EQ. 1 .AND. DV .LE. 4.5 .AND. DV .GT. 3.5) THEN
-
Y=PR4
-
-
ENDIF
-
IF(FLAG .EQ. 1 .AND. DV .LE. 3.5 .AND. DV .GT. 2.5) THEN
-
Y=PR3
-
-
ENDIF
-
IF(FLAG .EQ. 1 .AND. DV .LE. 2.5 .AND. DV .GT. 1.5) THEN
-
Y=PR2
-
-
ENDIF
-
IF(FLAG .EQ. 1 .AND. DV .LE. 1.5 .AND. DV .GT. 0.5) THEN
-
Y=PR1
-
-
ENDIF
-
IF(FLAG .EQ. 1 .AND. DV .LE. 0.5) THEN
-
Y=PR0
-
-
ENDIF
-
; Predicted Sorg
-
IPRED=PR0*0+PR1+PR2*2+PR3*3+PR4*4+PR5*5
-
; SSAT conditionned on orgasm
-
INT6=THETA(6)
-
INT7=THETA(7)
-
INT8=THETA(8)
-
INT9=THETA(9)
-
E2=THETA(10)*IPRED**2+THETA(17)*BSS+THETA(11)*(1–EXP(–THETA(16)*TIME))
-
E2=E2+EXP(THETA(19))*ETA(2)
-
A6=INT6+E2
-
A7=INT7+E2
-
A8=INT8+E2
-
A9=INT9+E2
-
; Cummulative probabilities
-
PS2=EXP(A6)/(1+EXP(A6))
-
PS3=EXP(A7)/(1+EXP(A7))
-
PS4=EXP(A8)/(1+EXP(A8))
-
PS5=EXP(A9)/(1+EXP(A9))
-
; Probabilities
-
PC1=1–PS2
-
PC2=PS2–PS3
-
PC3=PS–PS4
-
PC4=PS4–PS5
-
PC5=PS5
-
; Likelihood
-
IF(FLAG .EQ. 0 .AND. DV .GT. 4.5) Y=PC5
-
IF(FLAG .EQ. 0 .AND. DV .LE. 4.5 .AND. DV .GT. 3.5) THEN
-
Y=PC4
-
-
ENDIF
-
IF(FLAG .EQ. 0 .AND. DV .LE. 3.5 .AND. DV .GT. 2.5) THEN
-
Y=PC3
-
-
ENDIF
-
IF(FLAG .EQ. 0 .AND. DV .LE. 2.5 .AND. DV .GT. 1.5) THEN
-
Y=PC2
-
-
ENDIF
-
IF(FLAG .EQ. 0 .AND. DV .LE. 1.5 .AND. DV .GT. 0.5) THEN
-
Y=PC1
-
-
ENDIF
-
$THETA
-
...
-
$OMEGA 1 FIXED 1 FIXED
-
$EST MAXEVALS=9000 PRINT=5 POSTHOC NOABORT METHOD=COND LAPLACE LIKE
-
$COV
Rights and permissions
About this article
Cite this article
Claret, L., Cox, E.H., McFadyen, L. et al. Modeling and Simulation of Sexual Activity Daily Diary Data of Patients with Female Sexual Arousal Disorder Treated with Sildenafil Citrate (Viagra®). Pharm Res 23, 1756–1764 (2006). https://doi.org/10.1007/s11095-006-9007-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-006-9007-4