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Antimicrobial Agents and Chemotherapy, March 2000, p. 752-755, Vol. 44, No. 3
Department of Infectious Diseases, University
of Genoa, Genoa,1 4th Pediatric Clinic,
University of Milan, Milan,2 and
Virology Laboratory, Istituto Superiore di Sanita',
Rome,3 Italy
Received 4 February 1999/Returned for modification 22 August
1999/Accepted 29 November 1999
The indinavir dosage regimen currently used for human
immunodeficiency virus (HIV)-infected children is not based on
pharmacokinetic data obtained in the target patient population. The
purpose of our study was to characterize indinavir pharmacokinetics and
pharmacodynamics in HIV-infected children. Eleven children (age range,
9.0 to 13.6 years; weight range, 21.7 to 56.0 kg) receiving indinavir
(500 mg/m2 every 8 h) in combination with lamivudine
and stavudine were studied. The correlation of indinavir
pharmacokinetic parameters and demographic parameters was evaluated.
Also, the pharmacodynamic relationship between parameters of indinavir
exposure and parameters of renal toxicity and immunologic recovery was
studied. The area under the indinavir concentration-time curve (AUC)
and patient body surface area (BSA) showed a significant negative
correlation (r = 0.73; P = 0.012). Patients with smaller BSA had excessive indinavir AUC
compared to adults. On the other hand, the median minimum drug
concentration in plasma (Cmin) was lower than
that reported for adults. The maximum indinavir concentration in serum was higher in patients with renal toxicity (5 out of 11 children), but
the difference was not statistically significant (15.3 ± 8.2 versus 9.8 ± 4.4 mg/liter; P = 0.19). There was
a trend toward higher immunologic efficacy in patients with greater
indinavir exposure: the time-averaged AUC of the percentage of
CD4+ lymphocytes over the baseline value for patients with
indinavir Cmin > 95% inhibitory
concentration (IC95) was higher than in patients with
Cmin < IC95
(P = 0.068). Our study suggests that a dose reduction
may be appropriate for children with small BSA and that a 6-h dosage
regimen may be indicated for a substantial percentage of patients. Due
to the low number of patients enrolled in this study, our results
should be confirmed by a larger study.
Indinavir is a potent antiretroviral
drug belonging to the family of protease inhibitors. Although the body
of literature regarding the clinical efficacy and toxicity of this drug
in adults is considerable, the usage in pediatric patients remains
anecdotal (6, 7, 9, 10). An overview of the published
experience with indinavir in pediatric patients indicates that the
efficacy profile may be comparable to the one reported for adult
patients, while renal toxicity occurs more frequently, with up to 44%
of the patients experiencing renal side effects (6, 7, 10) compared to approximately 5 to 10% of adults.
In the studies cited above, indinavir was administered at a dose of 500 mg/m2 every 8 h (q8h). This dosage regimen was
inferred from the one used for adults but is not based on
pharmacokinetic (PK) data obtained with the target population. The
purpose of our study was to characterize the PK profile of indinavir in
human immunodeficiency type 1 (HIV-1)-positive children and to evaluate
(i) the relationship of PK parameters with demographic parameters and
(ii) the relationship of parameters of systemic exposure to indinavir
with parameters of efficacy and toxicity.
Patients.
Eleven children vertically infected with HIV-1 were
enrolled in the study after parental written informed consent was
obtained. The patients enrolled in this study represent a subset of 25 patients enrolled in a pilot study of which the results regarding
immune reconstitution and viral suppression have been recently
presented (A. Vigano', M. Clerici, D. Bricalli, M. Sarasella, S. Difabio, N. Principi, and S. Vella, 12th World AIDS Conf., abstr. 12247).
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Copyright © 2000, American Society for Microbiology. All rights reserved.
Indinavir Pharmacokinetics and Parmacodynamics in
Children with Human Immunodeficiency Virus Infection
ABSTRACT
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Virologic and immunologic assessment. Plasma viral load was quantified using the branch DNA assay (Chiron, Emeryville, Calif.) with a lower limit of quantification of 400 copies/ml. The CD4+ lymphocyte count and the percentage of CD4+ lymphocytes with respect to the overall lymphocyte cell population (%CD4) were determined by means of flow cytometry with Coulter (Coulter Electronics, Inc., Miami Lakes, Fla.) or Ortho (Ortho Diagnostic System) flow cytometry. Viral load, CD4+ lymphocyte count, and %CD4 were measured at the baseline and at 1, 3, 6, 9, and 12 months after the beginning of indinavir treatment.
Toxicity evaluation. Clinical (flank pain, renal colic) and laboratory (serum creatinine, hematuria, crystalluria, pyuria, casts) signs of renal toxicity possibly due to indinavir were recorded at each visit throughout the 12-month follow-up period. Additionally, total bilirubin was recorded at the baseline and at 1, 3, 6, 9, and 12 months following indinavir treatment initiation.
PK study.
Patient demographics at the time of PK study, as
well as the baseline viral load, the CD4+ cell count, and
%CD4 are shown in Table 1. The body mass
index (BMI) was calculated as weight/height2. A complete
medical history, a physical examination, and a panel of laboratory
tests consisting of a chemistry screen and a complete blood cell count
with differential and platelet counts were carried out within a week
before the PK study. None of the patients had diarrhea at the time of
the PK study. None of the patients had received drugs known or
suspected to interact with indinavir PKs in the 2 weeks before the PK
study began. None of the patients had signs of acute infection in the 1 month before the PK study began.
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Drug administration and sample collection. The dose of indinavir (Merck Sharp & Dohme, Rome, Italy) administered to each patient was the closest approximation to the dose calculated based on the recommended dose of 500 mg/m2 of body surface area (BSA) q8h. The 200- or 400-mg capsules commercially available for use by adults were used. At the time of the PK study, the patients had been treated with the same indinavir dosage regimen for at least 3 months. On the day of the PK study, the patients fasted for at least 2 h before and at least 1 h after indinavir administration.
Blood samples (5 to 7 ml) were collected in preheparinized Vacutainer tubes at 0 (predose), 0.5, 1, 1.5, 2, 4, and 8 h following drug administration. Blood samples were placed on ice and centrifuged within 30 min after collection. The plasma was harvested and stored at
70°C until assayed for indinavir.
Analytical methods. Indinavir concentrations were determined by means of a newly developed high-pressure liquid chromatography assay. Indinavir sulfate powder for laboratory use and an appropriate internal standard (L-707-943) were provided by Merck Sharp & Dohme. Briefly, indinavir extraction from plasma samples was done by addition of phosphate buffer to 0.5 ml of plasma (50:50, vol/vol), followed by elution of the mixture through Extrelut-1 columns (Merck, Darmstadt, Germany) using diethyl ether. Eluates were evaporated to dryness, reconstituted in the mobile phase, and injected onto a Supelcosil LC ABZ column (Supelco, Inc., Bellefonte, Pa.). UV detection was done at a wavelength of 220 nm.
The standard curve ranged from 0.025 to 15 mg/liter. The interday and intraday variabilities at concentrations of 0.085, 0.75, 3, and 8 mg/liter (quality controls) were less than 10%. Samples with concentrations above the upper limit of the standard curve were diluted 1:2 and reprocessed. Dilution did not affect quantitation at the quality control concentration of 30 mg/liter (n = 6).PK analysis. Indinavir PK parameters were obtained by noncompartmental methods using the program SIPHAR (Simed, Inc., Creteil, France). The area under the concentration-time curve (AUC) from time zero to 8 h following drug administration was calculated by use of the trapezoidal rule. The elimination rate constant was calculated as 0.693/lambda, where lambda was obtained by unweighted linear regression of the terminal linear portion of the concentration-versus-time curve. Clearance/bioavailability was calculated as the absolute dose administered divided by the AUC. Maximum concentration (Cmax), time to Cmax, and concentration at 8 h following administration (Cmin) were obtained by visual inspection of the data.
Statistical analysis was carried out on a MacIntosh computer using the program Staview II (Abacus Concepts Inc., Berkeley, Calif.). All demographic and PK data are reported as means ± SD. A value of P < 0.05 was considered the cutoff for significance. The Pearson correlation coefficient obtained by unweighted linear regression was used to evaluate the correlation between indinavir AUC and patient BSA.Pharmacodynamic (PD) analysis. (i) Efficacy.
The relationship
between the indinavir log-transformed AUC and parameters of immunologic
response (CD4+ lymphocyte count and %CD4 recovery over a
12-month follow-up period) was studied by means of linear regression.
%CD4 was considered because children may have physiologic
lymphocytosis. Therefore, %CD4 may be a more reliable parameter of
disease progression and treatment efficacy than the absolute
CD4+ cells count in this particular patient population. The
CD4+ cell count and %CD4 recovery were quantified in terms
of the time-normalized AUC over the baseline and the difference between the maximum value observed over the follow-up period and the baseline value (
max). The following covariables were tested,
besides the indinavir AUC, for effect on the CD4+ cell
count and %CD4 recovery: patient age, BSA, BMI, baseline CD4+ cell count, %CD4, and viral load. Multivariate
analysis was carried out by stepwise linear regression. Also, the
relationship between indinavir Cmin and the
parameters of CD4+ cell count and %CD4 recovery was
analyzed by dichotomizing the patients depending on whether the
Cmin was above or below the reported 95%
inhibitory concentration of 0.075 mg/liter (ca. 100 nmol/liter)
(3). Data were compared using the two-tailed unpaired t test.
(ii) Toxicity.
The relationship between the parameters of
indinavir exposure and the parameters of renal toxicity was evaluated
by dichotomizing the patients into two groups depending on the presence
or absence of signs of renal toxicity over the study period. The
dependence of total bilirubin levels on the parameters of indinavir
exposure was analyzed by parameterizing bilirubin as baseline
normalized bilirubin AUC and max.
Results of PK analysis.
The PK parameters of indinavir in the
11 study patients are shown in Table 1. For seven of the plasma
concentration-versus-time curves (Fig.
1), the half-life could be calculated
only on the basis of two terminal points. Therefore, the confidence in
this parameter estimate should be considered low. The median predose concentration and the concentration at 8 h following
administrations were 0.081 and 0.073 mg/liter, respectively. The
indinavir AUC was negatively correlated with BSA (r = 0.73;
P = 0.012). None of the PK parameters was associated with the
actual daily dose of indinavir.
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Results of PD analysis. (i) Efficacy.
All of the patients
showed substantial immunologic recovery. The median (range)
max for CD4+ cell count and %CD4 were 317 (148 to 617) cells/µl and 11.3% (3.8 to 24.8%). Indinavir AUC and
Cmax were tested after log transformation. The
parameters of CD4+ cell count and %CD4 recovery appeared
to be positively correlated with parameters of indinavir exposure, even
though none of the relationships was statistically significant. It is
noteworthy that the indinavir AUC showed a positive correlation with
CD4+ max (r = 0.49; P = 0.12) and %CD4 AUC (r = 0.45, P = 0.17) and max (r = 0.43, P = 0.14). Patients
with a Cmin lower than the IC95 had
a lower %CD4 AUC (P = 0.068) and max
(P = 0.068).
max, because for the other parameters of %CD4 recovery,
none of the covariables tested resulted in a significant correlation.
Baseline viral load was the better predictor of %CD4
max, while indinavir AUC remained out of the model.
(ii) Toxicity. Five (45.5%) of the 11 children had at least one episode of renal side effects over the 1-year follow up. Toxicity ranged from mild to severe: patients 4, 5, and 6 complained of flank or abdominal pain without evidence of kidney stones; patient 7 had renal colic, one 2-mm kidney stone, and a mild transient increase in serum creatinine (from 0.7 to 1.0 mg/dl) when the renal colic occurred. Patient 3 had one episode of renal colic with macrohematuria, had recurrent leukocyturia, and subsequently developed acute renal failure, defined as a persistent increase in the serum creatinine level to greater than 0.5 mg/dl above the baseline value. Indinavir treatment of patient 3 was discontinued, and his renal failure completely resolved within 3 months of indinavir withdrawal. All patients received indinavir for at least 1 year. All patients except patient 3 continued treatment with indinavir after the 1-year follow-up period.
There was a trend toward a higher indinavir AUC and Cmax in patients who had renal side effects. The indinavir AUC was 53.6 ± 37.7 mg × h/liter in patients with renal side effects versus 30.2 ± 12.9 mg × h/liter in patients with no side effects (P = 0.18). The Cmax was 15.3 ± 8.2 mg/liter in patients with renal side effects versus 9.78 ± 4.4 mg/liter in patients without side effects (P = 0.19). Notably, the patient with a higher indinavir Cmax and AUC (patient 7) had a kidney stone. None of indinavir exposure parameters correlated with parameters of bilirubin alteration. Bilirubin AUC andmax were highly correlated with baseline bilirubin (r = 0.84 and P = 0.001 and
r = 0.77 and P = 0.005, respectively).
The dosage regimen of a drug to be administered to children is usually
calculated with the goal of achieving parameters of drug exposure
comparable to those of adults, with the assumption that similar drug
exposure will result in comparable efficacy and toxicity. Our study
indicates that the indinavir dosage regimen of 500 mg/m2
does not achieve this goal in HIV-infected children. In fact, in our
study, the indinavir AUC and Cmax were higher,
on average, than those reported in the literature for adult patients
(8; E. P. Acosta, K. Henry, D. Weller, L. M. Page, L. Bacon, F. Rhame, I. Gilson, H. Rosenstein, T. Schacker, and C. V. Fletcher, Abstr. 37th Intersci. Conf.
Antimicrob. Agents Chemother., abstr. A-15; G. Gatti, A. Di Biagio, C. De Pascalis, E. Pontali, M. Bassetti, M. Cruciani, and D. Bassetti,
Abstr. 38th ICAAC, abstr. A66) treated with the standard dosage regimen
of 800 mg q8h. For example, the average AUC reported for adults is 20 mg × h/liter. Also, it is noteworthy that the indinavir exposure
parameters found in our study varied over a wide range, in agreement
with another study (6), with some patients having
particularly high values.
The negative correlation we found between indinavir AUC and BSA
indicates that a dose of 300 to 400 mg/m2 q8h may be more
appropriate for children with smaller BSA in order to avoid excessive
drug exposure. A larger study should be conducted in order to estimate
a precise BSA cutoff. Also, it is noteworthy that 6 of the 11 patients
had a Cmin below the reported mean 95%
inhibitory concentration of indinavir for HIV. This observation
suggests that the total daily dose, particularly in the case of a dose
reduction, as we advise, should be administered in four doses in order
to obtain a higher Cmin and therefore reduce the
risk of treatment failure. In a study, this approach was used for 75%
of the patients (6) as an intervention based on individual Cmins observed following administration of the
standard dosage regimen. To date, however, dosage regimen
individualization based on drug concentrations in plasma is not
applicable in everyday clinical practice because of the lack of a
suitable assay for such a setting.
Monitoring of plasma drug concentrations and dosage adjustment are
particularly relevant when a correlation between parameters of drug
exposure and drug effect (efficacy and/or toxicity) can be
demonstrated. It is a subject of debate whether the efficacy of
indinavir may be predicted by parameters of drug exposure. Most
researchers report that virologic response to indinavir correlates with
parameters of drug exposure such as Cmin and AUC
(11; Acosta et al., 37th ICAAC; D. M. Berger,
R. M. W. Hoetelmans, J. W. Mulder, P. L. Meenhorst,
P. W. H. Hugen, K. Brinkman, and P. P. Koopmans, 12th
World AIDS Conf., abstr. 42275; R. Murphy, J.-P. Sommadossi, M. Lamson, P. Gagnier, D. Hall, M. Myers, and A. Dusek, 12th World AIDS
Conf., abstr. 22404; M. Harris, C. Durakovic, S. Rae, S. Fransen, A. Shillington, B. Conway, and J. S. G. Montaner, Abstr. 37th
ICAAC, abstr. I-173), while others cannot find such a relationship (J. Chodakewitz, P. Deitsch, R. Leavitt, J. McCrea, M. Nessly, A. Sterrett, and G. Winchell, 12th World AIDS Conf., abstr. 42266; L. Perello, C. Goujard, J. F. Delfraissy, and A. M. Taburet,
12th World AIDS Conf., abstr. 42272). Our study shows a trend toward a
more favorable immunologic response in patients who had higher indinavir exposure. A classical maximum-effect
(Emax) model was not used because preliminary
analysis showed that such a model did not result in improvement of fit
compared to linear regression. It has to be noted that parameters of
indinavir immunologic efficacy were regressed versus log parameters of
indinavir exposure, which is also considered a useful approach applied
to pharmacodynamic analysis with the purpose of linearizing the central
portion of the Emax relationship, i.e., the
portion of the curve included between 20 and 80% of the
Emax (5). It is noteworthy that the patients enrolled in this PK-PD substudy, as well as all of the patients in the main clinical study, responded extremely well both from
a virologic standpoint, with prolonged and sustained suppression of
viral replication, and in terms of immune reconstitution, with a major
increase in CD4+ cell count, CD4+ naive cells,
expansion of the TRC
repertoire on CD4+ cells, and
improvement of peripheral blood mononuclear cell proliferative response
to recall antigens (Vigano' et al., 12th World AIDS Conf.). Also, a
recovery of thymus dimension was observed (Vigano' et al., 12th World
AIDS Conf.).
A significant relationship has been reported both for indinavir
(2) and ritonavir (4) exposure versus renal
toxicity (indinavir) and gastrointestinal and/or neurological side
effects (ritonavir). In our study, indinavir AUC and
Cmax showed only a trend toward higher values in
patients with signs of renal toxicity compared with patients without
renal toxicity. It is noteworthy that indinavir PKs were not studied on
the day of occurrence of renal signs or symptoms. Therefore,
intraindividual PK variability may have partially blunted the
relationship between parameters of indinavir exposure and renal
toxicity. Recently, a study with adults (2) reported that
indinavir plasma concentrations were significantly higher in 12 out of
15 patients with renal side effects than those observed in a reference
population without renal side effects. For five of these patients, the
dose was reduced to 600 mg q8h.
In conclusion, our PK-PD study shows that (i) indinavir, used in
combination with stavudine and lamivudine, has potent antiretroviral efficacy in pediatric patients and (ii) patients had
higher-than-expected exposure, particularly those with smaller BSAs,
and this may be the cause of the higher efficacy but also of a higher
risk of renal toxicity, compared to that of adults. Our study suggests that a dose of 300 to 400 mg/m2 q8h would be more
appropriate for patients with small BSAs. However, for a substantial
percentage of patients, a q6h dosage regimen may be more strongly
indicated. In this perspective, the development of an indinavir assay
suitable for therapeutic drug monitoring in everyday clinical practice
is needed in order to select patients for whom such a dosage regimen
may be indicated. Our data should not be extrapolated to patients with
BSAs outside the range observed in this study. Also, due to the low
number of patients enrolled in this study, our results should be
confirmed by a larger study.
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ACKNOWLEDGMENTS |
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This study was supported by grants 30A.0.07 and 30A.0.56 from the Istituto Superiore di Sanita' (Italian NIH).
We thank Franca Miletich for her skillful assistance with the indinavir high-pressure liquid chromatography assay.
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FOOTNOTES |
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* Corresponding author. Mailing address: Clinica di Malattie Infettive-Pad 9 F, Ospedale San Martino, Largo R. Benzi 10, 16132 Genova, Italy. Phone: 011-39-10-353 7677. Fax: 011-39-10-353 7680. E-mail: gigatti{at}smartino.ge.it.
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Antimicrobial Agents and Chemotherapy, March 2000, p. 752-755, Vol. 44, No. 3
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Copyright © 2000, American Society for Microbiology. All rights reserved.
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