Nelfinavir pharmacokinetics in HIV-infected children: a comparison of twice daily and three times daily dosing

The safety, efficacy and tolerance of antiretroviral triple therapy with two nucleoside reverse transcriptase inhibitors (NRTI) and the protease inhibitor nelfinavir mesylate (NFV) has been well documented. Paediatric studies with a three times daily application of NFV showed a profound and lasting antiviral effect and a good toxicity profile [1–4]. In adults, pharmacokinetic studies showed sufficient plasma levels of NFV for doses of 750 mg three times a day and 1250 mg twice a day [5–8]. NFV pharmacokinetics in children are rare. Studies with 20–30 mg/kg three times daily administration showed approximately equal [2], higher [9], or body weight-dependent plasma levels, with higher levels for children weighing over 25 kg [10] compared with adults. A paediatric study showed higher plasma NFV levels for twice daily compared with three times daily administration [10]. In this open prospective study, 18 HIV-infected children (11 male, seven female) aged 2–14 years (mean:10 years) classified as categories A (n = 12), B (n = 3) and C (n = 3) according to the Centers for Disease Control and Prevention guidelines were enrolled. At the start of the study all children had received two NRTI and NFV for a mean duration of 14.5 months (range 5–24). The mean CD4 cell count was 774/μl (range 0–1607) and the median viral load was 150 copies/ml (range < 20–75 000). Morning NFV three times daily pharmacokinetics were performed 0, 1, 2, 4, and 8 h post-dose. All children were then switched to two times daily administration, and after 4 weeks pharmacokinetics were repeated under similar conditions 0, 1, 2, 4, and 12 h post-dose. Viral load (Amplicor-test 2, Hoffman-La Roche, Grenzach-Whylen, Germany), CD4 cell count (flow-cytometry, monoclonal antibodies, Becton Dickinson, Heidelberg, Germany), serum triglyceride and cholesterol levels were monitored every 4–8 weeks over a mean period of 8 months (range 4–12). For further evaluation patients were subdivided into two groups according to body weight: group I over 25 kg (n = 10) and group II less than 25 kg (n = 8). Children weighing less than 25 kg received 30–37 mg/kg NFV three times a day or 45–55 mg/kg twice a day, as recently recommended by the manufactorers (Agouron, La Jolla, CA, USA), children weighing over 25 kg received 750 mg three times a day or 1250 mg twice a day. NFV was given with food as tablets (n = 13) or oral powder (n = 5). The pharmacokinetics and oral bioavailabilities of the two formulations seemed to be similar [2]. NRTI were given in the recommended dosage. Quantification of NFV in plasma was performed by tandem mass spectrometry combined with high-speed on-line high-performance liquid chromatography (Professor Kurowski, Berlin, Germany) [11,12]. Adult studies showed sufficient Cmin and Cmax values ranging from 1000 to 3000 ng/ml and 3000 to 4000 ng/ml, respectively [13]. Changing NFV application was well tolerated in all children. At the onset and end of the monitored period stable median values were found: viral load 150 and 225 copies/ml, CD4 cell count 774 and 756/μl, triglyceride levels 192 and 182 mg/dl, cholesterol levels 132 and 143 mg/dl, respectively. Plasma NFV levels are given in Fig. 1. Statistics were drawn using the Wilcoxon rank-sum test. NFV twice a day showed higher plasma levels at each measurement point. Mean values for all children for twice daily and three times daily administration were: Cmin 1774 and 880 ng/ml (P < 0.005), Cmax 3977 and 2682 ng/ml (P < 0.025), Ctrough (C12 for twice daily, C8 for three times daily) 1893 and 1548 ng/ml (P > 0.1; not significant), area under the plasma concentration-time curve (AUC0−−24 h) 66 466 and 47 331 ng/h per ml (P < 0.025).Fig. 1.: (a) Mean plasma nelfinavir mesylate levels of all children (n = 18). (b) Mean plasma nelfinavir mesylate levels of group I (> 25 kg bodyweight) (n = 10). (c) Mean plasma nelfinavir mesylate levels of group II (< 25 kg bodyweight) (n = 8). Horizontal lines show the recommended plasma nelfinavir mesylate levels: Cmin 1000–3000 ng/ml; Cmax 3000–4000 ng/ml. - - - ▵ - - -, twice a day administration; —▪—, three times a day administration.In twice daily application, 14 out of 18 (78%) and 11 out of 18 (61%) reached the recommended Cmin and Cmax values, whereas in three times daily application only four out of 18 (22%) and seven out of 18 (39%) reached the recommended values. Comparing the groups, significant differences at each measurement point between twice daily and three times daily administration were found in group I (Fig. 1b), but not in group II (Fig. 1c). Mean values for group I for twice daily and three times daily administration were: Cmin 1708 and 984 ng/ml, Cmax 4060 and 2167 ng/ml, AUC0−−24 h 68 032 and 39 054 ng/h per ml (all P < 0.05). Values for group II were: Cmin 1857 and 764 ng/ml (P < 0.025), Cmax 3873 and 3325 ng/ml, AUC0−−24 h 65 056 and 58 062 ng/h per ml (both P > 0.1; not significant). These pharmacokinetic data obtained from a small study cohort supports twice daily administration because of higher Cmin, Cmax and AUC0−−24 h values, as reported by Hayashi et al. [10]. AUC0−−24 h for three times daily administration was comparable to adult studies, as reported by Krogstad et al. [2]. Changing NFV application was more effective in children weighing over 25 kg. The different pharmacokinetic results found between groups I and II may be caused by higher drug clearance rates in small children [10]. Therefore higher NFV dosages (90–110 mg/kg per day) are needed in children weighing less than 25 kg to achieve sufficient plasma levels. Taking antiretroviral drugs exactly every 8 h seems to be difficult for children. Insufficient morning plasma levels found in the three times daily group may be caused by larger dosing intervals during the night, other day-time dosing intervals may be shorter, with higher peak and trough concentrations. This leads to suboptimal dosing, which increases the risk of developing resistance. In a twice daily regimen, plasma levels are more balanced and drugs are easier to take (no drug administration at school or kindergarden). In children, it is particularly important to find therapeutic regimens that are adapted to their normal life. A twice daily regimen of all antiretroviral drugs appears to meet these criteria and should therefore increase compliance. Tobias Schustera Richard Lindea Uwe Wintergerstb Markus B.