Methylphenidate

Additional information

Pharmacokinetics and dosing

In a population pharmacokinetic study in children with ADHD (212 boys, 61 girls; age 5-18 years), clearance and half-life of methylphenidate were similar in boys and girls receiving the same mean daily dose [6]. However, results from studies in adult healthy volunteers show that when the doses are normalized to the body weight (mg/kg), females have lower systemic exposure (AUC) [7-9]. In addition, one study has reported no differences in AUC between males and females receiving the same total dose, even though women generally weigh less. The major metabolite, ritalinic acid, was greater in females [10].

Studies in adult women have identified lower plasma concentrations of methylphenidate after weight based dosing, relative to men [9,11]. In a two-way crossover study (10 men, 9 women), each subject received both a 20 mg and 18 mg extended-release methylphenidate dose. The average mg/kg dose in the males was approximately 30% less than in females, yet the mean AUC was not different between sexes. Since the half-life between the sexes was also the same, it could be speculated that more extensive first-pass metabolism of methylphenidate occurs in females [7]. These findings suggest that some women may require higher mg/kg doses to achieve the same methylphenidate plasma concentration as men [1, 8]. However, it is not clear whether both sexes require similar plasma concentrations to achieve the same therapeutic objective [7].

Effects

Small studies have shown that the response to methylphenidate in girls with ADHD is comparable to that in boys with ADHD [1,11-14]. These studies suggest that the tolerability and safety of methylphenidate is similar in males and females.A double-blind, placebo-controlled study  investigated sex differences in attention performance in ADHD children (27 boys, 27 girls) treated with methylphenidate (0.25 vs. 0.5 mg/kg, single dose). Boys were more impulsive on a sustained attention task, whereas girls with ADHD had more deficits on tasks measuring selective attention. No differences in methylphenidate efficacy were observed between boys and girls with ADHD [15].One study has examined sex differences in response to two once-daily methylphenidate formulations in children (136 boys, 48 girls). Girls had superior response at 1.5 hours after drug administration and an inferior response at 12 hours relative to boys. Sex was independent of drug formulation. The responses of girls may require additional assessments later in the day to determine the optimal dose [16].Children with ADHD and anxiety disorders in absence of other comorbidities are less likely to respond to methylphenidate, according to a randomized, double-blinded, placebo-controlled study (208 boys, 59 girls). Results were irrespective of sex [17].

Adverse effects

A randomized, double-blind, placebo-controlled study (19 men, 16 women; age 16-19 years) found no sex differences in report of side effects. This suggests that tolerability and safety of methylphenidate is similar in males and females [1, 13].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

Even though earlier studies of ADHD treatment included few females, recent RCTs to demonstrate efficacy in the newer ER preparations have enrolled reasonable numbers of females [1]. In a large European observational study, fewer girls than boys were referred for ADHD treatment, but they were as likely as boys to receive stimulant medication as an initial treatment for ADHD [2]. In Sweden, the ratio of boys to girls receiving license prescriptions for AHDH medications is 4:1 [3].A study on prescription patterns of medications for ADHD in Sweden from 2006 to 2009 (methylphenidate, atomoxetine, amphetamine or dexamphetamine) showed that the prescribing prevalence increased more among women than men over the years (prevalence ratio 2.92 vs. 2.19). There were no differences in treatment discontinuation between men and women [4].Drug treatment of ADHD in children and youth in Germany was evaluated in a study. Time until first prescription of methylphenidate or atomoxetine was different between sexes: > 50 % of males received treatment within 30 months of diagnosis, while the corresponding time for > 50 % of females was 48 months [5].A small study (6 men, 6 women) examined sex differences in response to short-acting methylphenidate (0.5 mg/kg) on energy intake in young healthy adults (18-40 years) with normal weight or higher. Relative to placebo, men exhibited a significantly greater reduction in energy intake, fat intake and carbohydrate intake after methylphenidate administration, compared to women [18].