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Drug Design, Development and Therapy Volume 8, 2014 - Issue
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Original Research

Pilot Phase II study of mazindol in children with attention deficit/hyperactivity disorder

Eric Konofal1 Pediatric Sleep Disorders Center, Hôpital Robert Debré, Assistance Publique – Hôpitaux de Paris (APHP), Paris, France;2 Child and Adolescent Psychiatric Department, Hôpital Robert Debré, Assistance Publique – Hôpitaux de Paris (APHP), Paris, France
,
Wei Zhao3 Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Assistance Publique – Hôpitaux de Paris (APHP), Paris, France;4 Clinical Investigation Center, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France;5 Université Paris Diderot, Sorbonne Paris Cité, Paris, France
,
Cédric Laouénan5 Université Paris Diderot, Sorbonne Paris Cité, Paris, France;6 INSERM, Infection, Antimicrobiens, Modélisation, Evolution (IAME), UMR1137, Paris, France;7 Department of Biostatistiques, Hôpital Bichat, APHP, Paris, France
,
Michel Lecendreux1 Pediatric Sleep Disorders Center, Hôpital Robert Debré, Assistance Publique – Hôpitaux de Paris (APHP), Paris, France;2 Child and Adolescent Psychiatric Department, Hôpital Robert Debré, Assistance Publique – Hôpitaux de Paris (APHP), Paris, France
,
Florentia Kaguelidou3 Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Assistance Publique – Hôpitaux de Paris (APHP), Paris, France;4 Clinical Investigation Center, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France;5 Université Paris Diderot, Sorbonne Paris Cité, Paris, France
,
Lila Benadjaoud4 Clinical Investigation Center, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
,
France Mentré5 Université Paris Diderot, Sorbonne Paris Cité, Paris, France;6 INSERM, Infection, Antimicrobiens, Modélisation, Evolution (IAME), UMR1137, Paris, France;7 Department of Biostatistiques, Hôpital Bichat, APHP, Paris, France
&
Evelyne Jacqz-Aigrain3 Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Assistance Publique – Hôpitaux de Paris (APHP), Paris, France;4 Clinical Investigation Center, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France;5 Université Paris Diderot, Sorbonne Paris Cité, Paris, FranceCorrespondence[email protected]
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Pages 2321-2332 | Published online: 11 Dec 2014

Figures & data

Table 1 Demographic and baseline characteristics for the 21 children

Figure 1 Distribution of Attention Deficit/Hyperactivity Disorder Rating Scale (ADHD RS-IV) scores of the 21 patients before (screening and baseline), at the end (visit 3), and after stopping the treatment (visit 4).

Note: Box and whisker plots illustrate mean (+ sign within box), median (line through the center of box), 75th percentile (top line of box), 25th percentile (bottom line of box), 1.5 times the interquartile range (bars projecting up and down from the box), and outlier values falling outside 1.5 times the interquartile range (stars above and below box and whisker).
Figure 1 Distribution of Attention Deficit/Hyperactivity Disorder Rating Scale (ADHD RS-IV) scores of the 21 patients before (screening and baseline), at the end (visit 3), and after stopping the treatment (visit 4).

Figure 2 Distribution of Conners’ Parent Rating Scale – Revised: Long (CPRS-R:L) of the 21 patients before (screening and baseline), at the end (visit 3), and after stopping the treatment (visit 4).

Notes: There was a single follow-up visit, visit 4. The CPRS-R:L score was completed by the parents on a weekly basis, three times during the follow-up (at day 14 for the day 7–14 period, at day 21 for the day 14–21 period and at day 28 for the day 21–28 period). Box and whisker plots illustrate mean (+ sign within box), median (line through the center of box), 75th percentile (top line of box), 25th percentile (bottom line of box), 1.5 times the interquartile range (bars projecting up and down from the box), and outlier values falling outside 1.5 times the interquartile range (stars above and below box and whisker).
Figure 2 Distribution of Conners’ Parent Rating Scale – Revised: Long (CPRS-R:L) of the 21 patients before (screening and baseline), at the end (visit 3), and after stopping the treatment (visit 4).

Figure 3 Distribution of Clinical Global Impression – Severity (CGI-S) score of the 21 patients before (screening and baseline), at the end (visit 3), and after stopping the treatment (visit 4).

Note: Box and whisker plots illustrate mean (+ sign within box), median (line through the center of box), 75th percentile (top line of box), 25th percentile (bottom line of box), 1.5 times the interquartile range (bars projecting up and down from the box), and outlier values falling outside 1.5 times the interquartile range (stars above and below box and whisker).
Figure 3 Distribution of Clinical Global Impression – Severity (CGI-S) score of the 21 patients before (screening and baseline), at the end (visit 3), and after stopping the treatment (visit 4).

Table 2 Clinical Global Impression – Improvement scores after 1 week of mazindol (1 mg/day) in the 21 patients

Figure 4 Individual observed plasma concentrations of mazindol (ng/mL) versus time.

Note: Concentrations were measured at day 1 after first dose administration and at day 7 12–48 hours after last dose administration. The number of below-the-limit-of-quantification observations was added under the x-axis for each time period.
Figure 4 Individual observed plasma concentrations of mazindol (ng/mL) versus time.

Figure 5 Diagnostic goodness-of-fit plots for the pharmacokinetic model of mazindol.

Note: (A) Observed (DV) versus population predicted concentrations (PRED), observed versus individual predicted concentrations (IPRED), and weighted residuals (WRES) and normalized prediction distribution error (NPDE) versus time. Below-the-limit-of-quantification (BLQ) observations were removed from the plots. (B) Visual predictive check (VPC) for the mazindol final model. Observed data are plotted using circles (°). BLQ observations were replaced by half the limit-of-quantification value (0.25 ng/mL) for the VPC plots. The dashed lines represent the 10th, 50th, and 90th percentiles of simulated data (n=1,000). The solid lines represent the 10th, 50th and 90th percentiles of observed data.
Figure 5 Diagnostic goodness-of-fit plots for the pharmacokinetic model of mazindol.

Table 3 Population pharmacokinetic parameters of mazindol estimated in 21 children: basic model with no covariates, final model, and associated bootstrap results

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