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Modeling and Simulation of Sexual Activity Daily Diary Data of Patients with Female Sexual Arousal Disorder Treated with Sildenafil Citrate (Viagra®)

Pharmaceutical Research Aims and scope Submit manuscript

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.

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Correspondence to Lynn McFadyen.

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

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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

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  • DOI: https://doi.org/10.1007/s11095-006-9007-4

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