TABLE 2.

Details of study population, study objectives, methodology, and results of trials identified to have a primary objective of exploring sex‐differences in pharmacokinetic parameters for anticholinergic medications

Study author & design	Study population	Study objective	Methodology	Results
Vicente et al. 97 Randomized single‐lind controlled trial	24 healthy non‐smoking volunteers (12 women and 12 men), 18–35 years old	To determine if quinidine induced prolongation of the time from the peak to the end of the T‐wave is greater in women than men	Subjects received either 4 mg/kg of quinidine IV or a matching placebo solution over 20 min with 28 blood samples and simultaneous ECGs collected after drug/placebo infusion for each subject at predetermined time points over the following 12 h	Quinidine causes QTc prolongation and T‐wave morphology changes in both women and men Quinidine‐induced maximum QTc (541 ± 40 ms vs. 510 ± 38 ms; p = .07) or maximum T peak–T end (216 ± 60 ms vs. 222 ± 37 ms; p = .76) was similar for men and women There was a trend toward a lower maximum serum quinidine concentration in women compared with men (2.9 ± 0.7 μg/ml vs. 3.7 ± 1.2 μg/ml; p = .07) The slope describing serum quinidine concentration versus QTc prolongation was greater in women than in men (38 ± 10 ms/μg/ml vs. 28 ± 9 ms/μg/ml; p = .02) Differences between women and men occurred primarily in the first 20 min after quinidine infusion, when serum quinidine concentrations were higher in men than women
Benton et al. 95 Randomized single‐blinded controlled trial	24 healthy non‐smoking volunteers (12 women and 12 men), 18–35 years old	To determine if women have larger increases in QT interval than men at equivalent serum concentrations of quinidine after intravenous administration	Subjects received either 4 mg/kg of quinidine IV or a matching placebo solution over 20 min. 28 blood samples and simultaneous ECGs were collected after drug/placebo infusion for each subject at predetermined time points over the following 48 h	There was a trend to greater weight‐adjusted clearance of quinidine in women than in men (5.2 ± 1.1 ml/min/kg vs. 4.3 ± 1.6 ml/min/kg) There was also a trend to a higher maximal plasma concentration of quinidine in men than in women (3.67 ± 0.13 μg/ml vs. 2.78 ± 0.87 μg/ml; p = .07) There were no sex‐related differences in the ratio of the AUC∞ of 3‐hydroxyquinidine to the AUC∞ of quinidine The estimated volume of distribution (V d) at steady state was not different between the men and women There was no difference in the free fraction of quinidine in serum between men and women The free fraction of 3‐hydroxyquinidine was slightly higher in women than in men (0.53 ± 0.05 μg/ml vs. 0.47 ± 0.05 μg/ml; p < .01)
Winchell et al. 98 A series of open‐label, three‐period, randomized, crossover studies	1. 24 healthy young subjects (mean age: 25.5 years; range: 19–39 years; 16 males and 8 females 2. 18 healthy subjects (mean age: 28.7 years; range: 22–40 years; 8 males, 10 females) 3. 12 elderly subjects (mean age: 71.3 years; range: 65–79 years; 6 males, 6 females	To investigate the pharmacokinetics and bioavailability of cyclobenzaprine, including the effects of sex and age	1. Bioavailability: Subjects received 5 mg orally or 1.25 mg IV cyclobenzaprine 2. Pharmacokinetics: Subjects received a single oral dose of 2.5, 5, or 10 mg cyclobenzaprine on Day 1 then every 8 h from Days 8 through 14 with final dose on Day 15 3. Pharmacokinetics in aging: Subjects received 5 mg cyclobenzaprine orally three times daily for 7 days and a final dose on Day 8	1. Plasma concentrations increased initially, peaking at 4 h post dose, and then declined slowly Mean plasma clearance was 689 ± 216 ml/min—Mean oral bioavailability 5 mg tablet formulations were 0.55 (90% CI [0.51, 0.60]) 2. There were no statistically significant differences between males and females for any of the pharmacokinetic parameters—AUC(0–8 h) and C Max after the last dose were marginally significantly different between sexes 3. The population‐by‐sex effect was marginally significant for AUC(0–8 h) (p = .056) but not for C Max
El‐Eraky et al. 96 Open trial	48 healthy volunteers (27 men, 21 women) aged 18–64 years	To determine why women are more susceptible to QT interval prolongation and torsade de pointes after administration of drugs that delay cardiac repolarization	All subjects took quinidine sulfate capsules 3 mg/kg orally then ECGs and blood samples for quinidine concentrations were taken over 24 h following drug administration	There were no significant differences in quinidine concentrations between men and women or in any of the pharmacokinetic variables measured The QTa, and QTc intervals were larger in females than in males Quinidine did not affect QRS duration in women but reduced QRS duration in men
Koren et al. 122 Single‐center, single dose open‐label, reference replicate bioavailability study	12 healthy males and 12 healthy females, 18–45 years with a body mass index between 19–30 kg/m2	To determine the effect of sex on the pharmacokinetics of doxylamine–pyridoxine 10–10 mg delayed‐release tablets	Participants were given doxylamine–pyridoxine 20–20 mg delayed‐release tablets with 240 ml water on an empty stomach with blood sampling starting 1 h pre‐dose with samples analyzed using high performance liquid chromatography‐ tandem mass spectrometry	Females had significantly larger AUC0– t for doxylamine compared with males A higher C Max for doxylamine was observed in females compared with males
Malhotra et al. 118 Two randomized double‐blind placebo‐controlled trials	1. 32 healthy males aged 18–45 years 2. 16 young men, 16 older men and 16 older women	To examine the effect of age, sex and race on the pharmacokinetics, pharmaco‐dynamics and safety profiles of fesoterodine	Subjects received either 8 mg of fesoterodine extended release or placebo with blood samples drawn over 36 h after drug administration and saliva samples on cotton wool collected over 24 h after drug administration	No apparent differences in C Max, AUC0–∞, t max, or mean residual time between males and females Total plasma clearance was highest in young men and lowest in older women Elderly women experienced a 1 g decrease in salivary volume and elderly men did not 5 h after dose Elderly men experienced the greatest residual urinary volume increase 8 h after dose
Ebert et al. 123 Open label crossover study	7 men and 7 women of mean age 23 years and in good health	To identify any pharmacokinetic differences between male and female volunteers in the metabolism of scopolamine when given with grapefruit juice	Each subject received at random scopolamine 0.5 mg IV, scopolamine 0.5 mg orally, or scopolamine 0.5 mg orally mixed with 150 ml fresh grapefruit juice and blood sampling occurred over the 24 h following drug administration	C Max was significantly higher in males than females (6.61 ng/ml vs. 3.93 ng/ml) after IV infusion All other parameters were similar
Macleod et al. 99 Open label study	4 men and 5 women aged 21–30 years, and 5 older men and 5 older women aged 70–88 years	To identify age and gender differences in diazepam pharmacokinetics	10 ml blood samples were taken over 1 week after receiving 0.125 mg/kg diazepam IV over 10 min	There was a significant difference in plasma clearance between men and women (male: 33.2 ml/min and women: 18.1 ml/min) The half‐life in men (32 h) was significantly shorter than in women (46.2 h) V d was not significantly different between sexes
Bigos et al. 100 Naturalized prospective study	332 men and 191 women who were using olanzapine for AD or schizophrenia	To evaluate population pharmacokinetics of olanzapine and factors that contribute to variability in exposure including sex, race and smoking status	Plasma levels of olanzapine were determined and then used to calculate non‐linear mixed effects modelling for pharmacokinetic analysis	Men cleared olanzapine 38% faster than women (p < .0001, unpaired t test)
Hartter et al. 105 Prospective study	15 male and female participants with major depression	To assess sex differences in fluvoxamine serum concentration at two different fixed dosing regimens (50 twice daily and 100 mg twice daily)	Drug monitoring after 14 days of either treatment	There was a significantly greater increase in fluvoxamine serum concentration in men than in women when the dose doubled (4.6‐fold vs. 2.4‐fold increase)

Abbreviations: AUC, area under the curve; IV, intravenous.