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Pharmacokinetics and Pharmacodynamicsof Nelfinavir Administered Twice or ThriceDaily to Human Immunodeficiency VirusType 1–Infected Children G. Gatti,1,a G. Castelli-Gattinara,2 M. Cruciani,3 S. Bernardi,2 C. R. De Pascalis,1 E. Pontali,1 L. Papa,1 F. Miletich,1
and D. Bassetti1

1Gaslini Childrens Hospital, Genoa, 2Bambin Gesu` Childrens Hospital, Rome, and 3Center of Preventive Medicine/HIV Outpatient Clinic,Verona, Italy We studied the pharmacokinetics and pharmacodynamics of nelfinavir administered 2 or 3 times per day to
human immunodeficiency virus type 1 (HIV-1)–infected children receiving highly active antiretroviral therapy
containing nelfinavir. The geometric mean trough concentrations of nelfinavir for the thrice- and twice-daily
regimens were 1.55 mg/L and 1.11 mg/L, respectively (P
p not significant). Nelfinavir concentrations did not
correlate with total daily dose, dose per kilogram of weight, age, weight, previous protease inhibitor (PI)
experience, or CD4+ cell percentage. In the 25 PI-naive children, the virus load reductions at 24 weeks of
treatment with the twice- and thrice-daily regimens were comparable. A significantly higher percentage of
children in the twice-daily group had a trough concentration of nelfinavir of less than the inhibitory concen-
tration of 95% (P
p .042). The decrease in the virus load at 24 weeks of treatment was not correlated with
the trough concentration of nelfinavir. The variability of trough concentrations was extremely high, particularly
among recipients of the twice-daily regimen, resulting in a higher number of patients with subinhibitory
concentrations of nelfinavir in this group.

Although several aspects of HIV infection are similar macokinetics of nelfinavir have been investigated in for patients of all age groups, pediatric HIV infection healthy volunteers and in HIV-infected adults [2, 9, 10].
requires special considerations with respect to epide- Data on the pharmacokinetics of nelfinavir in children miological, clinical, pharmacokinetic, and therapeutic with HIV infection are scarce [3, 4, 6, 11–13]. In older issues [1]. Nelfinavir is one of the currently available children, administration of nelfinavir at a dosage of protease inhibitors (PIs) used for the treatment of HIV ∼20–30 mg/kg 3 times per day provides exposure sim- infection in both adults and children [2–8]. The phar- ilar to a dosage of 750 mg 3 times per day for adults.
Nelfinavir has recently been approved for a twice- daily dose regimen for adults, whereas, for pediatricpatients, twice-daily administration is being studied [1].
Received 25 August 2002; accepted 10 February 2003; electronically published However, the pharmacokinetics of twice-daily admin- istration of nelfinavir to children is limited to prelim- Financial support: Istituto Superiore di Sanita´, Rome (grant 30C8), and a grant from Gaslini Children’s Hospital, Genoa, Italy.
inary reports [4, 11, 12]. Because a twice-daily regimen a Present affiliation: Vertex Pharmaceuticals, Cambridge, Massachusetts.
may improve adherence to treatment, additional eval- Reprints or correspondence: Dr. Giorgio Gatti, Malattie Infettive, Nuovo uation of the pharmacokinetics of twice-daily regimens Isolamento Ospedale San Martino, 16132 Genova, Italy (gatti@vpharm.com).
of nelfinavir in children is timely and relevant.
Clinical Infectious Diseases
2003; 36:1476–82
The present study was designed to evaluate pharma- 2003 by the Infectious Diseases Society of America. All rights reserved.
cokinetic and pharmacodynamic data for HIV-1–infected 1476 • CID 2003:36 (1 June) • HIV/AIDS
children receiving HAART that involves twice- or thrice-daily (for 20 children). The drug was taken with food, as recom- administration of nelfinavir. The pharmacokinetic study aimed to assess the variability of plasma concentrations of nelfinavir Adherence to the treatment regimen and dietary require- for the administered regimen. In the pharmacodynamic study, ments was evaluated at every visit by an interview conducted we focused on the relationship between the trough concentra- by the care givers. Only patients defined as compliant with tion of nelfinavir and the virologic response in PI-naive treatment (compliance of у95%) were included in the analysis Obtainment of blood samples for nelfinavir concentration
analysis.
Blood samples (5–7 mL) were drawn into prehe- parinized vacutainer tubes before a morning dose of nelfinavir PATIENTS, MATERIALS, AND METHODS
of the morning dose. All samples were obtained 9–16 weeks This open-label prospective study was conducted at 2 large after the initiation of nelfinavir treatment. At the time of study, Italian children’s hospitals (Istituto G. Gaslini, Genoa, and Os- none of the children had diarrhea or had received drugs known pedale Pediatrico Bambin Gesu`, Rome). The study protocol or suspected to interact with nelfinavir.
was approved by the local institutional review boards of both Analytical methods.
institutions. Written informed consent was obtained from the were determined using a validated high-performance liquid parents or guardians of the children before study entry. The chromatography (HPLC) assay. In brief, standard curves and pharmacokinetic portion of the study aimed to evaluate the quality-control samples were prepared using nelfinavir powder variability of plasma concentrations of nelfinavir after twice- (kindly donated by Agouron Pharmaceuticals). Samples were or thrice-daily administration and to correlate nelfinavir con- loaded onto a 10-mg, 96-well Oasis MCX Extraction Plate (Wa- centrations with potential predictors of patient exposure to the ters), washed with acidified water, and then washed with ace- drug. The pharmacodynamic portion of the study was limited tonitrile. Elution was performed with a basic mixture of ace- to PI-naive children and designed to evaluate the relationship tonitrile and methanol; the samples were evaporated to dryness between trough concentration of nelfinavir and virologic re- under a gentle stream of nitrogen. The extracts were redisolved sponse after twice- or thrice-daily administration of nelfinavir.
in a mobile phase of phosphate buffer (25 mmol/L; pH, 5) and Study subjects.
The study population included 35 children acetonitrile (55:45 v/v) for direct injection into the HPLC sys- vertically infected with HIV-1, regardless of disease classifica- tem. Nelfinavir was separated with a 5-mm Symmetry Shield tion [14]. Twenty-five children were PI naive, and the remaining Column (Waters) at a flow rate of 1.5 mL/ 10 were PI experienced. To be eligible for enrollment in the min (L-7100 LaChrom Pump; Merck-Hitachi). The detector study, children had to have been receiving nelfinavir for у1 (L-4200 UV-VIS; Merck-Hitachi) was set at a wavelengh of 210 month before study entry. Before study entry, a complete med- nm. Chromatography was performed at room temperature ical history was obtained, a physical examination was done, (20ЊC–25ЊC). All reagents were HPLC gradient grade.
and a panel of laboratory tests, which consisted of a chemistry Peaks of interest were quantified using a TurboChrom Nav- screening and a complete blood cell count with differential and igator 4.0 Chromatography Data System (Perkin Elmer). The concentration standard curve was prepared in the range of Virologic and immunologic assessment.
0.1–15 mg/mL. Precision (intraday and interday variabilities; lymphocyte count, and CD4+ cell percentage were measured at 9 of the assay was !10% at each of the quality-control baseline and every 12 weeks. The plasma virus load was de- concentrations (0.75, 3, and 10 mg/mL). The average recovery termined using the branched DNA assay (Chiron), which has was 78.6%, and the lower limit of quantification was 0.1 mg/ a lower limit of quantification of 400 copies/mL. The CD4+ lymphocyte count and the percentage of CD4+ lymphocytes, Pharmacokinetic, pharmacodynamic, and statistical analy-
with respect to the overall lymphocyte count (CD4+ cell per- sis.
The data obtained from all 35 study patients were used centage), were determined using Coulter (Coulter Electronics) for pharmacokinetic analysis. The baseline characteristics of or Ortho (Ortho Diagnostic System) flow cytometry kits.
children receiving the twice- or thrice-daily nelfinavir regimen Drug administration.
were analyzed using x2 test, Fisher’s exact test, and Student’s t were receiving nelfinavir tablets in combination with 2 nucle- test. Peak and trough concentrations of nelfinavir after twice- oside analogue reverse-transcriptase inhibitors (NRTIs) or daily administration were compared with concentrations after NRTI(s) plus a nonnucleoside reverse-transcriptase inhibitor.
thrice-daily administration using the Mann-Whitney U test.
The dosage of nelfinavir administered to each patient was the Correlations of plasma concentrations of nelfinavir with dem- closest approximation to the recommended dosages of 20–30 ographic and other potentially predictive variables were ex- mg/kg every 8 h (for 15 children) and 50 mg/kg every 12 h plored using the Pearson correlation coefficient, which was HIV/AIDS • CID 2003:36 (1 June) • 1477
Baseline demographic and clinical characteristics of children in the study.
CDC HIV disease stage, no. (%) of patients CDC, Centers for Disease Control and Prevention.
a Patients were protease inhibitor naive.
obtained by unweighted regression analysis. The following var- iables were tested: total daily dose, dose per kilogram of bodyweight, dosage regimen (twice-daily vs. thrice-daily), age, Study populations.
Thirty-five children were enrolled in the weight, previous PI experience, and baseline CD4+ cell per- study during the period of February 1999 through September centage. The percentage of CD4+ cells was considered because 2000. Baseline patient characteristics are shown in table 1. Of children may have had physiological lymphocytosis. Therefore, the 35 children, 10 were PI experienced and 25 were PI naive.
the CD4+ cell percentage may be a more reliable parameter of This subgroup of 25 patients was included in the pharmaco-dynamic analysis.
disease progression and treatment efficacy than is the absolute Twenty children (14 of whom were PI naive) received nel- CD4+ cell count in this particular population. Multivariate finavir at a mean dosage of 47.2 mg/kg twice per day (range, analysis was performed using the stepwise multiple regression 32.9–62.5 mg/kg b.i.d.). Fifteen children (11 of whom were PI test when the result of univariate analysis was statistically naive) received a mean dosage of 25.8 mg/kg 3 times per day (range, 17.4–35.7 mg/kg t.i.d.). No statistically significant dif- Only the 25 PI-naive children were included in the phar- ferences were found between patients receiving twice-daily reg- macodynamic analysis. The virus load was measured at baseline imens and those receiving thrice-daily regimens with regard to and after 24 weeks of nelfinavir therapy. The relationship be- age, sex, previous PI experience, weight, baseline CD4+ cell tween virologic response (virus load at 24 weeks minus the percentage, total number of CD4+ cells, HIV-1 infection clas- virus load at baseline) and trough concentration of nelfinavir sification group (by Centers for Disease Control and Prevention was evaluated by linear and nonlinear regression. Also, the criteria), and baseline virus load (table 1).
percentage of patients with trough concentrations that were less A variety of antiretroviral combinations were administered than the mean nelfinavir concentration to produce 95% in- concomitantly with nelfinavir, including didanosine and sta- hibition of viral replication (IC ) was compared for the twice- vudine (10 children); stavudine and lamivudine (12 children); daily and thrice-daily regimens. Because the activity of nelfi- zidovudine and lamivudine (5 children); stavudine, lamivudine, navir is reduced significantly in the presence of human serum, and nevirapine (1 child); stavudine and nevirapine (2 children); we used the wild-type, protein binding–corrected IC (1 mg/ stavudine and zalcitabine (2 children); zidovudine and abacavir L), as estimated in the presence of 50% human serum [15, 16].
(2 children); and lamivudine and abacavir (1 child). At the Statistical calculation was performed on a MacIntosh com- time of initiation of nelfinavir treatment, 7 children were an- puter using the Staview II program (Abacus Concepts). A P tiretroviral therapy naive, 21 children modified all underlying value of !.05 was considered the cutoff for statistical sig- NRTIs, 6 children added nelfinavir to their treatment regimens, 1478 • CID 2003:36 (1 June) • HIV/AIDS
Peak and trough plasma concentrations of nelfinavir.
regimen group (P p .042, by 2-tail Fisher’s exact test; figure 2, There was a large interpatient variability in plasma concentra- tions of nelfinavir. Plasma samples with peak nelfinavir con- At 24 weeks of follow-up, we observed a mean virus load centrations were obtained 3.7 ע 2.2 h after nelfinavir admin- reduction (עSD) of 2.8 ע 0.7 log copies/mL in the twice- daily regimen group, compared with a reduction of 2.1 ע 1.2 regimen group (geometric mean, 5.65 mg/L), compared with log copies/mL in the thrice-daily regimen group. This differ- 2.24–11.72 mg/L in the thrice-daily regimen group (geometric ence was not statistically significant.
mean, 4.00 mg/L). This difference was not statistically sig- On univariate analysis, the decrease in the virus load at 24 weeks of treatment was not correlated with trough concentra- The relationship between trough plasma concentrations and tion of nelfinavir. There was, however, a trend toward a de- administered dose is depicted in figure 1. The geometric mean creased virus load in patients with higher trough concentrationsof nelfinavir (figure 3).
trough concentration for the thrice-daily regimen group (1.55mg/L; range, 0.13–5.22 mg/L) was not significantly differentthan that for the twice-daily regimen group (1.11 mg/L; range, DISCUSSION
nondetectable to 6.08 mg/L). In the whole population exam- We studied the variability of plasma concentrations of nelfinavir ined, peak and trough concentrations of nelfinavir did not cor- after twice-daily and thrice-daily dosing, the correlation of relate with total daily dose, dose per kilogram of weight, age, plasma concentrations with potential predictors of patient ex- weight, previous PI experience, or CD4+ cell percentage.
posure to the drug, and the relationship between trough con- Pharmacodynamic
study.
centrations of nelfinavir and virologic response, according to SD for the 25 PI-naive children in the twice-daily 14 and thrice-daily (n p 11) groups, respectively, were In our study of 35 children, we found an extremely high as follows: age, 8.1 ע 3.0 versus 6.3 ע 2.5 years; weight, interindividual variability in trough and peak concentrations 20.2 ע 6.9 versus 21.6 ע 7.1 kg; baseline CD4+ cell percentage, of nelfinavir, as was already observed in adults and in small 20.6% ע 10.7% versus 26.3% ע 12.0%; and baseline virus cohort studies of children [2, 4, 6, 11–13, 17, 18]. We did not load, 5.1 ע 0.4 versus 5.2 ע 0.8 log copies/mL. Mean dosages identify factors that could explain the observed variability in of nelfinavir were 48.7 mg/kg twice per day (range, 33.3–62.5 plasma concentrations of nelfinavir. Despite the high dose range mg/kg b.i.d.) and 27.6 mg/kg 3 times per day (range, 21.4–35.7 used, peak and trough concentrations did not correlate with mg/kg t.i.d.), respectively. Geometric mean trough concentra- total daily dose and dose per kilogram of weight, nor with age, tions of nelfinavir in the twice- and thrice-daily regimen groups weight, previous PI experience, and CD4+ cell percentage. Pos- were 0.94 mg/L (range, not detectable to 5.74 mg/L) and 1.63 sible sources of variation in plasma concentrations are attrib- mg/L (range, 0.13–5.22 mg/L), respectively. Seven (50%) of 14 utable to peculiar pharmacokinetic properties of nelfinavir. Be- children in the twice-daily regimen group had a trough con- cause the drug has relatively slow gut absorption, peak and centration of nelfinavir of !1 mg/L (estimated IC trough concentrations may occur after the C value), compared with 1 (9%) of 11 children in the thrice-daily ples have been obtained [19]. Moreover, as already observed Figure 1.
The relationship between nelfinavir (NFV) dose per kilogram of body weight and predose plasma concentration of NFV HIV/AIDS • CID 2003:36 (1 June) • 1479
Figure 2.
The trough concentrations of nelfinavir in protease inhibitor–naive children receiving nelfinavir thrice (top) or twice (bottom) per day.
Horizontal line, protein binding–corrected concentration producing 95% inhibition of viral replication (IC ) of nelfinavir (1 mg/L) for wild-type virus.
with other PIs, the variability of nelfinavir concentrations may in the twice-daily regimen group. Eight (40%) of 20 patients reflect the interindividual variability in the activity of the P450 in the twice-daily regimen group, compared with 2 (13%) of enzyme system metabolizing the drug and the extent of its 15 patients in the thrice-daily regimen group, had a trough saturability. It should be noted that, in our study, nevirapine concentration that was less than the wild-type, protein bind- was coadministered to 3 children (2 in the thrice-daily regimen of 1 mg/L [15, 16]. Although the limit of group and 1 in the twice-daily regimen group); however, this this approach should be acknowledged, particularly in the pres- drug did not appear to influence nelfinavir metabolism in vivo ence of drug-resistant virus, the finding of a trough plasma level that was less than the minimum effective concentration In our study, trough and peak concentrations did not differ should be recognized as a clear indication of treatment inad- between regimen groups. Although this was an observational study without randomized design, it is unlikely that the design Because there is evidence showing a relationship between introduced an important bias. Our results are in agreement virologic outcome and plasma concentration of PIs [19], we with the results of other studies that have compared concen- investigated the effect of thrice-daily versus twice-daily admin- trations of nelfinavir after administration of twice-daily and istration of nelfinavir on virologic response. Because previous thrice-daily regimens in children [4, 11, 12] and adults [18].
exposure history may affect the emergence of drug-resistant Of interest, we found that the interindividual variability in HIV variants, in this part of the study, we included only PI- the plasma concentration of nelfinavir was even more evident 1480 • CID 2003:36 (1 June) • HIV/AIDS
Figure 3.
The relationship between the decrease in the virus load at 24 weeks of treatment and trough concentrations of nelfinavir (NFV) in protease inhibitor–naive children.
Overall, patients responded well to treatment. The mean re- of nelfinavir daily dose and concomitant antiretroviral drugs duction in the virus load did not differ significantly between received, may also be regarded as a source of variability. On recipients of the twice-daily regimen and recipients of the the other hand, the study was aimed at harvesting data reflecting thrice-daily regimen, despite there being a significantly higher number of children in the twice-daily regimen group with Although the lack of correlation between virologic outcome trough concentrations that were less than the IC . Also, the and exposure would suggest that TDM may not be of benefit decrease in the virus load at 24 weeks of treatment did not for this particular clinical setting, the above description of con- correlate with trough concentrations of nelfinavir, even though founding factors should mitigate this conclusion. In fact, the we observed a trend toward a better response in patients with high interindividual variability in plasma concentrations is in favor of TDM, as a recent study also suggests [21].
In the present study, there are several factors that can explain In conclusion, our study confirms the unpredictability of the lack of difference in virologic response between recipients plasma concentrations of nelfinavir. The variability of trough of twice-daily regimens and recipients of thrice-daily regimens, concentrations was extremely high, particularly in the twice- as well as the lack of correlation between exposure and response.
daily regimen group, resulting in a higher number of patients First of all, the number of PI-naive children was too low to who had a trough concentration less than the IC in the twice- detect significant differences in virologic response between daily regimen group, compared with the thrice-daily regimen group. Despite this difference in exposure, the virologic re- exposure. In fact, in some patients, the plasma concentration sponse at 24 weeks of treatment was similar for the 2 dosage of PIs continues to decay after drug administration because of regimens in PI-naive children. A number of confounding fac- delayed absorption. Moreover, the utility of estimating single tors may explain the lack of correlation between nelfinavir ex- plasma drug concentrations (trough or random sample) is un- posure and virologic response. Therefore, our study does not clear at this time [19]. Third, in our study, we did not monitor exclude the utility of TDM, which is instead suggested by the the M8 nelfinavir metabolite, although this procedure does not high interindividual variability in plasma concentrations.
seem to be essential for the purpose of therapeutic drug mon-itoring (TDM) [17]. Fourth, we did not provide data on in-tracellular concentration of antiretroviral drugs and on the pos- References
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