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PEDIATRICS |
From Hoffmann–La Roche, Inc, Nutley, New Jersey (Dr Zhang, Dr Lin, Ms Bertasso, Mr Kolis, Dr Salgo, Dr Patel); Roche Products Ltd, Welwyn Garden City, UK (Ms Evans); and XIQ Coordination, Inc, Fort Myers, Florida (Dr Dorr).
Address for reprints: Xiaoping Zhang, PhD, Hoffmann–La Roche Inc, 340 Kingsland Street, Nutley, NJ 07110; e-mail: Xiaoping.zhang{at}roche.com.
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ABSTRACT |
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Key Words: Enfuvirtide • population pharmacokinetics • pediatric • fusion inhibitors • human immunodeficiency virus • HIV • pharmacodynamics
In the HIV-1-infected adult patient population, enfuvirtide exhibits a small volume of distribution (5.48 L), low systemic clearance (1.4 L/h), and moderately high plasma protein binding (92%). Less than 17% of enfuvirtide is converted to a minimally active deaminated form of the parent drug. Both enfuvirtide and its metabolite are primarily eliminated via catabolism to amino acid residues. Following subcutaneous administration, enfuvirtide is almost completely absorbed, and exposure increases almost linearly with dose over the range of 45 to 180 mg. When administered at the recommended dose in adults, subcutaneous absorption is slow and protracted, resulting in relatively flat steady-state plasma concentration–time profiles. Bioavailability is high (84.3%), and the elimination half-life (3.8 hours) supports twice-daily (bid) dosing. Comparable absorption was observed from 3 different injection sites (upper arm, abdomen, and thigh). In adults, the pharmacokinetic–pharmacodynamic relationship indicates that the recommended dose of 90 mg bid injected subcutaneously, in combination with other active antiretrovirals, is optimum. Enfuvirtide clearance is influenced to a small extent by gender and body weight, but this does not necessitate dose adjustment. In vitro and in vivo studies indicate that enfuvirtide has a low potential to interact with concomitantly administered drugs. Enfuvirtide did not influence concentrations of drugs metabolized by CYP3A4, CYP2D6, or N-acetyltransferase and had only minimal effects on those metabolized by CYP1A2, CYP2E1, or CYP2C19. Coadministration of ritonavir, ritonavir-boosted saquinavir, or rifampicin did not result in clinically significant changes in enfuvirtide pharmacokinetics.5
Pharmacokinetic parameters analyzed using noncompartmental analysis methods from a subgroup of 25 HIV-1-infected pediatric patients, from the present study, have previously been reported. The previous analysis suggested that subcutaneous dosages based on body weight (2 mg/kg bid) produce pharmacokinetic profiles broadly similar to those observed in adults administered with 90 mg bid.6 The enfuvirtide Ctrough values were also shown to be stable over 24 weeks of treatment.7,8
The objective of the present analysis was to characterize the population pharmacokinetics of enfuvirtide and to investigate the effect of demographic factors on its pharmacokinetic variability in the overall cohort of HIV-1-infected pediatric patients in study T20-310/NV16056 over 48 weeks of treatment. This analysis was also planned to address whether the body weight–based dosing in the current dosing guidelines is justified.
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METHODS |
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5 and <12 years of age) or adolescents (12 and <17 years of age).
Study Patients
Pediatric patients with HIV-1 RNA 5000 copies/mL and a minimum of 3 months prior experience with at least 2 of the 3 other licensed antiretroviral drug classes (nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, or protease inhibitors) were eligible for inclusion in the study. Informed consent was obtained from each patient's parent or guardian and, in the case of patients who were aware of their HIV status and were above the age of assent per local regulations, from the patients themselves. The study protocol and consent procedures were approved by the relevant institutional review boards of the individual study centers.
Enfuvirtide Preparation and Administration
Enfuvirtide (Fuzeon®) was provided as a lyophilized powder in glass vials and was reconstituted at room temperature using 1.1 mL of sterile water for injection to achieve a final concentration of 45 or 90 mg/mL, depending on the vial size. The volume of enfuvirtide solution administered was dependent on the patient's weight. Parents or guardians were given detailed instructions for the preparation and administration of the reconstituted enfuvirtide and were required to demonstrate proficiency in administering SC injections. They were also instructed to rotate the body site used for injection. Use of a topical anesthetic (eg, Eutectic Mixture of Local Anesthetics [EMLA]) was allowed.
Pharmacokinetic Sampling Method
The first 12 patients enrolled per age group underwent intensive pharmacokinetic sampling at week 1 after reaching steady state. Plasma pharmacokinetic samples were drawn at predose and 2, 4, 8, and 12 hours following enfuvirtide administration. The blood samples for determination of Ctrough of enfuvirtide were collected at 12 ± 2 hours after enfuvirtide dose at weeks 2, 8, 16, and 24 for all patients. Not all patients returned for the 5 scheduled sparse samples. Four patients provided plasma samples after week 24. The actual sample dates and times were recorded in the case report form.
Analytical Method
Enfuvirtide plasma concentrations were measured at the Bioanalytical Division at MDS Pharma Services (Lincoln, Nebraska, USA) using a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method, which is described elsewhere.9 The lower limit of quantification was 10 ng/mL, and the calibration range of standard curves for enfuvirtide was 10 to 2000 ng/mL and 10 to 500 ng/mL for its deaminated metabolite. Interassay precision ranged from 3.8% to 7.9% for enfuvirtide and 4.4% to 13.4% for its metabolite. Overall accuracy (%Bias) ranged from –7.3% to 12.2% for enfuvirtide and –4.3% to 11.1% for its metabolite.
Population Pharmacokinetic Method
All patients and concentration–time data points were initially included into the database. Patients and/or data points were excluded on the basis of recording or operational errors only. Creatinine clearance was estimated via the method described by Cockcroft and Gault.10 All covariates assessed are shown in Table I.
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Both 1- and 2-compartment models were fit to the data using the first-order conditional estimate (FOCE) method.11 Covariate analysis was then carried forward using the best-fit base model. Addition of a covariate was accepted if it resulted in a reduction of the objective function by at least 10 points (P < .001) via the likelihood ratio test. Log-likelihood profiling was performed as a method of model qualification following identification of the final population pharmacokinetic (PK) model. Derived PK parameters included AUC12 h and Ctrough.
AUC12 h was calculated as
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Ctrough was calculated as
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is the dose interval of 12 hours, Ka is the first-order absorption rate constant, and V/F is the individual estimate for apparent volume of distribution. These parameters were obtained from the final model. For simplification, F (bioavailability) was assumed to be 1. Pharmacokinetic model building was conducted using NONMEM (Version V) with all recommended patches and bug corrections implemented. Digital Fortran 6.0A was the compiler used for the analysis. S-PLUS (Version 6.1) for Windows was used for plots.
Statistical Method
Comparison of the enfuvirtide exposures (AUC12 h and Ctrough) between children and adolescent age groups was performed using a Student t test of natural logarithmic-transformed values. The 2-tailed alpha was fixed at 0.05. Beta was fixed at 0.20, giving a power of 80%. Sample size (N) was fixed at 25, and sigma was estimated to be 16 µg/mL. This results in a delta of 35.9 µg/mL. Thus, the study had 80% power to detect a difference in the 2 population means of 35.9 µg/mL.
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RESULTS |
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Population Pharmacokinetic Database
A total of 239 enfuvirtide plasma concentration–time data from 45 patients were collected in study T20-310/NV16056. Of the 239 total enfuvirtide plasma concentrations available for analysis, 218 enfuvirtide concentrations from 43 patients (91.2% of the initially available observations and 95.6% of the total patients) are included. Two patients were excluded from the analysis due to irresolvable time-recording errors in the case report form.
Several structural and pharmacostatistical models to describe the time course of enfuvirtide concentrations were tested using FOCE with interaction. The final model selected was a 1-compartment model with first-order input and first-order elimination (ADVAN2 TRANS2) and with body weight as a covariate on CL/F. The model was parameterized for CL/F, V/F, and Ka with terms for interindividual variability on all parameters. Interindividual variability on Ka was fixed to 28.4% (estimate from base model) to achieve a successful covariance step. The model used a combined coefficient of variation (CCV) residual error model.
Body weight was identified as a covariate contributing to interindividual variability on CL/F.
The final model parameterization is shown in equations (1) to (3).
 | (1) |
 | (2) |
 | (3) |
1 is mean apparent clearance (L/h), 2 is mean apparent volume of distribution (L), 3 is mean absorption rate constant (h-1), and 4 is factor describing the effect of body weight (WT, kg) normalized to 33 kg on CL/F. The diagnostic plots for the final model are given in Figure 1. The observed (DV) versus predicted (PRED) enfuvirtide concentrations are evenly distributed about the line of unity (upper left panel). The plot of observed versus individual predicted concentrations (IPRE) (upper right panel) did not show noticeable improvement. The plot of absolute value of individual weighted residuals (IWRE) versus individual prediction concentrations (IPRE) (lower left panel) shows that there is a slight tendency for higher individual weighted residuals at lower concentrations. The plot of weighted residuals (WRES) versus time (lower right panel) did not suggest that there were any changes in model performance over time, and the majority of observations are within ±2 standard deviations.
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1), V/F (2), and Ka (3) for pediatric patients with a median weight of 33 kg was 1.31 L/h, 2.31 L, and 0.105 h–1, respectively. Interindividual variability was 36.2% for CL/F, 29.7% for V/F, and 28.4% for Ka. Random residual proportional variability was 41.0%. The allometric component for the effect of body weight normalized by median (33 kg) on CL/F was 0.721 (4).
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Estimated Enfuvirtide Exposures
Individual estimates of AUC12 h and Ctrough were calculated from individual CL/F derived from the final model. Across the body weight range from 13.8 to 78.3 kg, mean AUC12 h and Ctrough were 51.3 ± 16.1 h µg/mL and 2.69 ± 1.10 µg/mL, respectively. There was no statistically significant difference for either enfuvirtide AUC12 h or enfuvirtide Ctrough between the children and adolescent age groups (Table III and Figure 2). The exposures from the present analysis are similar to those achieved with the 90-mg bid dose in the HIV-1-infected adult population.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Conclusion
These findings confirm the current enfuvirtide pediatric dosing guidelines that children from 6 years of age should be treated with enfuvirtide at a dose of 2 mg/kg bid up to a maximum dose of 90 mg bid.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: Albert Dorr is an employee of XIQ Coordination, Inc, Fort Myers, FL. All other authors are employees of Roche.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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3. Lalezari JP, Henry K, O'Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med. 2003;348: 2175–2185.
4. Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med. 2003;348: 2186–2195.
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6. Bellibas SE, Siddique Z, Dorr A, et al. Pharmacokinetics of enfuvirtide in pediatric human immunodeficiency virus 1-infected patients receiving combination therapy. Pediatr Infect Dis J. 2004;23: 1137–1141.[Web of Science][Medline] [Order article via Infotrieve]
7. Zhang X, Dorr A, Siddique Z, Bertasso A, Rowell L, Kolis S. Pharmacokinetics (PK) and pharmacodynamics (PD) of enfuvirtide in HIV-1 infected adolescents over 24 weeks of treatment [abstract]. Clin Pharm Ther. 2004;75:26.
8. Zhang X, Lin T, Dorr A, et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of enfuvirtide in HIV-1-infected children over 24 weeks of treatment [abstract]. Clin Pharm Ther. 2005;77: 59.
9. Chang D, Kolis SJ, Linderholm KH, et al. Bioanalytical method development and validation for a large peptide HIV fusion inhibitor (Enfuvirtide, T-20) and its metabolite in human plasma using LC-MS/MS. J Pharm Biomed Anal. 2005;38: 487-496.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16: 31–41.[Web of Science][Medline] [Order article via Infotrieve]
11. Beal SL, Sheiner LB. NONMEM Users Guide, Part I-VIII: Technical Report. San Francisco: University of California, San Francisco; 1985.
12. Soy D, Aweeka FT, Church JA, et al. Population pharmacokinetics of enfuvirtide in pediatric patients with human immunodeficiency virus: searching for exposure-response relationships. Clin Pharm Ther. 2003;74: 569–580.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. Mould DR, Zhang X, Neiforth K, Salgo M, Buss N, Patel IH. Population pharmacokinetics and exposure-response relationship of enfuvirtide in treatment-experienced human immunodeficiency virus type 1–infected patients. Clin Pharm Ther. 2005;77: 515–528.[CrossRef][Web of Science][Medline]
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