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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey (Dr Yan, Dr Kaul, Dr Grasela); University of North Carolina, Chapel Hill, North Carolina (Dr Ataga, Dr Orringer); Bristol-Myers Squibb Pharmaceutical Research Institute, Plainsboro, New Jersey (Dr Olson, Dr Gothelf); and Medical College of Georgia, Augusta, Georgia (Dr Kutlar).
Address for reprints: Jing-He Yan, PhD, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543-4000.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Hydroxyurea • sickle cell disease • renal function
Several factors may contribute to the clinical severity in patients with SCD. The degree of adherence of sickle RBCs to the vascular endothelium has been shown to strongly correlate with the severity of disease in patients with sickle cell anemia.3 In addition, in patients with SCD, the RBCs contain varying amounts of different types of hemoglobin, particularly fetal hemoglobin (Hb F). Hemoglobin F is a very potent inhibitor of the polymerization of deoxyhemoglobin S. There is an inverse correlation between the frequency of painful crises and Hb F concentration in patients with SCD.4 Furthermore, high levels of Hb F have been reported to be associated with improved survival in these patients.5
Hydroxyurea is currently the only drug approved by the Food and Drug Administration (FDA) to treat SCD. The multicenter study of hydroxyurea (MSH) showed that hydroxyurea resulted in a significant decrease in the frequency and severity of painful crises, a reduction in the incidence of acute chest syndrome, and a reduction in the need for blood transfusions.6 Treatment with hydroxyurea has also been shown to result in substantial reduction in clinical events requiring hospitalization.7 Furthermore, hydroxyurea has recently been reported to result in reduced mortality in adults with severe sickle cell anemia.8
Hydroxyurea inhibits DNA synthesis by targeting ribonucleotide reductase, the enzyme responsible for the conversion of ribonucleotide diphosphates to the corresponding deoxyribose forms.9 Its exact mechanism of action in SCD is unknown. Although it is generally assumed that the benefit of hydroxyurea is due to an increase in Hb F levels, a multivariable analysis of data from the MSH showed that the percentage of F cells was inversely correlated with the rate of painful crises only during the first 3 months of therapy.10
As patients with SCD get older, they begin to manifest evidence of end-organ damage. Renal abnormalities are common in patients with SCD. Young patients manifest supranormal renal hemodynamics with elevation in both effective renal plasma flow and glomerular filtration rate.11 These parameters decrease with age as well as following the administration of prostaglandin inhibitors. Hydroxyurea is excreted via the renal route with a urinary recovery of approximately 35% of an orally administered dose in patients with normal renal function.12 Although it is relatively nontoxic, it can result in myelosuppression, which is readily reversible. There is a paucity of pharmacokinetic (PK) data with the use of hydroxyurea in patients with SCD, particularly in those patients with sickle cell anemia and varying degrees of renal function. To address the concern for potentially increased toxicity in those patients with various degrees of impaired renal function, the current study was conducted to assess the influence of renal function on PK of hydroxyurea in adults with sickle cell anemia after a single oral dose (15 mg/kg) of hydroxyurea. The PK results from the study were the basis for a recommendation to the FDA of a hydroxyurea starting dose modification in SCD patients with varying degrees of renal function impairment.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The protocol and informed consent were approved for use by the institutional review boards at the University of North Carolina, Chapel Hill and the Medical College of Georgia, Augusta.
Patients with SCD who had normal renal function (CLcr 
90 mL/min), mild renal impairment (CLcr = 60-89 mL/min), moderate renal impairment (CLcr = 30-59 mL/min), severe renal impairment (CLcr = 15-29 mL/min), or end-stage renal disease (ESRD) with a CLcr <15 mL/min or requiring maintenance hemodialysis were enrolled.13 The creatinine clearance (CLcr) was determined on 2 separate occasions based on 24-hour urine collections. The first (screening) CLcr was obtained on an outpatient basis no more than 1 month prior to enrollment and was used for eligibility. The second CLcr, which was performed on an inpatient basis on day 1 during the time of PK sampling, was used for strata determination and data analysis. Patients with SCD who had not previously received hydroxyurea and those who had previously been treated with hydroxyurea were eligible for participation in this study. Participants who had previously received hydroxyurea must not have taken hydroxyurea for at least 5 days prior to study day 1.
The other key inclusion criteria included male or female patients 18 years or older, females of childbearing potential using an acceptable method of contraception and with a negative serum or urine HCG test within 24 hours of the hydroxyurea dose, confirmed diagnosis of sickle cell anemia (HbSS) or sickle cell-beta zero thalassemia (HbSß0), weight 40 kg and no more than 15% below or 40% above ideal body weight, clinically acceptable laboratory values for hematology and serum chemistry for a patient with SCD, absence of evidence for acute illness, electrocardiogram (ECG) without clinically significant abnormalities, and no evidence of gastrointestinal impairment or previous gastrointestinal surgery (except for appendectomy and gallbladder surgery).
The key exclusion criteria included surgery within 4 weeks of enrollment; evidence of unstable cardiovascular, pulmonary, hepatic, hematologic, endocrine, or neurological illness; positive hepatitis B surface antigen; positive urine screen for drugs of abuse; evidence of acute or chronic pancreatitis; use of an agent known to affect renal tubular function within 2 weeks before enrollment; exposure to other investigational agents within 1 month of enrollment; and current or recent gastritis or diarrheal illness.
Patients who had normal renal function, as well as those with mild, moderate, or severe renal impairment, received a single 15-mg/kg dose of hydroxyurea (Droxia) administered as a combination of 200-mg, 300-mg, and 400-mg capsules. Blood and urine samples to assess hydroxyurea concentrations were obtained before hydroxyurea administration and at selected times up to 36 hours after the dose. Specifically, blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, and 36 hours postdose; urine samples were collected predose (spot urine) and at 0 to 6, 6 to 12, 12 to 24, and 24 to 36 hours postdose. Clinical evaluation, including clinical laboratory tests, was performed before dosing on day 1, before discharge from the study unit on day 2, and at follow-up (study discharge; 7-10 days after dosing).
Patients who had ESRD requiring maintenance hemodialysis were evaluated on 2 separate occasions. One dose of hydroxyurea (15 mg/kg) was given following a dialysis session, and blood samples to assess hydroxyurea concentrations were collected using the same schedule as for patients with the other 4 classifications of renal function. A second dose of hydroxyurea (15 mg/kg) was given 5 to 7 days later, 4 hours prior to a hemodialysis session. Blood samples to assess hydroxyurea concentrations were obtained predose and at 0.25, 0.5, 0.75, 1, 2, 4 (start dialysis), 4.5, 5, 6 (samples collected from both influx and efflux lines of the dialyzer), 7, 8 (end dialysis), 8.5, 9, 10, 12, 16, 24, 30, and 36 hours postdose. Clinical evaluation, including clinical laboratory tests, was performed before each dose, before discharge from the study unit after each dose, and at follow-up (study discharge).
Analytical Methods
Plasma samples were analyzed for hydroxyurea using a validated high-performance liquid chromatographic (HPLC) method with electrochemical detection. The calibration standards and quality control (QC) samples were prepared in commercially available KEDTA human plasma. The standard hydroxyurea used in the preparation of the standard and QC samples was obtained from Sigma Chemical Company (St. Louis, Mo). Standard x10 solutions (1, 2.5, 5, 10, 25, 50, 100, 150, and 200 µg/mL) were made by dilution, using water (HPLC grade), of the standard stock solution (1000 µg/mL), which was also made in water (HPLC grade). These standard x10 solutions and the stock solution were stored at 4°C (stable 12 days for the stock, 44 days for the standard x10). Quality control stock solution (1000 µg/mL, in HPLC grade water, same as the standard stock) was used to make the dilution QC (80 µg/mL) by adding 0.800 mL of QC stock into a 10-mL volumetric flask and diluting to volume with blank plasma. The dilution QC was used to make other QC samples (0.4, 8, and 16 µg/mL) by dilution with blank plasma. These QC samples were stored in a freezer at <-15°C (stable 16 days).
To each of 90 µL of blank plasma, 10 µL of the appropriate standard x10 was added to make the calibration standards at the following concentrations of 0.1, 0.25, 0.5, 1, 2.5, 5, 10, 15, and 20 µg/mL. For blank control samples, 100 µL blank plasma was used. Frozen study and QC plasma samples were thawed, shaken well, and then centrifuged for 5 minutes at 2600 rpm. For each of the study and QC samples, 100 µL plasma was added to a labeled culture tube. Dilution QC (80 µg/mL) was diluted with the same amount of plasma as used for the dilution of any high-concentration study samples or for at least 1:5. To each of the 100-µL plasma samples, 1000 µL of acetonitrile was added. The mixture was mechanically shaken for 20 seconds. All tubes were centrifuged for 5 minutes at 2600 rpm. Supernatants were decanted to a set of labeled culture tubes and were evaporated to dryness under nitrogen at 45°C and 20 psi for 15 minutes. The dried extracts were then reconstituted with 250 µL of mobile phase. The entire reconstituted extracts were transferred to autoinjector microinsert tubes, which were loaded into the autoinjector. The reconstituted extracts are stable for at least 24 hours at room temperature. Then, 40 µL of the reconstituted extracts was injected into a C-18 HPLC column, and hydroxyurea was measured by its electrochemical response at 0.6 V. The retention time for hydroxyurea was 
2.6 minutes.
The HPLC conditions are listed as follows. Column: Beckman Ultrasphere ODS, 5 µ, 250 x 4.6 mm; guard column: Brownlee RP-18, 7 µ, 15 x 3 mm; temperature: ambient or 25 °C; mobile phase: 5% acetonitrile in 50 mM sodium acetate, 5 mM tetrabutylammonium-hydrogen sulfate (TBAHS), pH 6.77; flow rate: 1.0 mL/min; detector: ESA coulochem, guard cell 0.65 V, 5011 analytical cell 0.6 V, 01x1; injection volume: 40 µL; cycle time set: 15 minutes; sampling rate: 2.0 pts/s; voltage input: 1 V; delay time: 0 minutes; runtime: 5 minutes; offset: 3.0 mV; scale: 50 mV; bunching factor: 2 points; area threshold: 1075 mV; noise threshold: 215 mV; quantitative units: µg/mL; curve: second-order fit; origin: ignored; scaling: 0; weighting: 1/x; abs. window: 0; rel. window: 5; calibration: external; response: height.
The assay was calibrated with each run. Standards of 9 concentrations plus a zero standard, in duplicate, were included. A weighted least squares quadratic regression was calculated on peak heights without the zero standard. Triplicate QC samples of 3 concentrations were included in each run. The deviation of the standard and QC samples must meet the following acceptance criteria. The acceptance criteria established for the analysis of hydroxyurea in plasma specified that the predicted concentrations of at least three fourths of the standards and two thirds of the QC samples be within ±15% of their individual nominal concentration values (±20% for the lowest concentration standard). If both of the lowest calibrators were rejected, the next higher level was to be subjected to the same criteria before the level could be accepted as the lower limit of quantitation (LLQ). In addition, at least 1 QC sample at each concentration level must be within ±15% of its individual nominal concentration value. In the event that diluted samples are assayed, diluted QC samples were also run in triplicate. The concentration of 2 of the diluted QC results must be within ±15% of the nominal value, or else all results from diluted samples in that run were declared invalid.
Urine samples were analyzed for hydroxyurea using a validated HPLC method with electrochemical detection. The calibration standards and QC samples were prepared in blank human urine. The standard hydroxyurea used in the preparation of the standard and QC samples was obtained from Sigma Chemical Company. A standard 500 solution (500 µg/mL) was made by weighing 25.0 mg of hydroxyurea, dissolving and diluting to volume with blank urine in a 50-mL volumetric flask. The standard 500 was diluted with blank urine in 10-mL volumetric flasks to make the following standards: 5, 10, 50, 200, 300, and 400 µg/mL. Quality control samples were made in a similar way at 3 concentrations (20, 200, and 400 µg/mL). These standard and QC samples were stored in a freezer at <-15°C (stable 16 days).
Frozen study, standard, and QC urine samples were thawed, shaken well, and then centrifuged for 5 minutes at 2600 rpm. For each of the study, standard, and QC samples, 100 µL was added to labeled culture tubes. The QC sample (400 µg/mL) was diluted with the same amount of urine as used for the dilution of any high-concentration study samples. The undiluted QC sample (400 µg/mL) was also included in the run when dilution QC was used. To each sample tube, 900 µL of mobile phase was added. The mixture was mechanically shaken for 20 seconds. Aliquots of 100 µL of each diluted study, standard, and QC samples were added to a second set of labeled culture tubes, followed by adding 900 µL of mobile phase and shaking mechanically for 20 seconds. Aliquots of 100 µL of each 1:100 diluted sample were added to autoinjector microinsert tubes, which were loaded into the autoinjector. The extracts are stable for at least 16 hours at room temperature. Then, 20 µL of the extracts was injected into a C-18 HPLC column, and hydroxyurea was measured by its electrochemical response at 0.6 V. The retention time for hydroxyurea was 2.6 minutes.
The HPLC conditions for the urine assay are the same as for the plasma assay, except for the following: injection volume, 20 µL; bunching factor, 4 points; area threshold, 156 mV; and noise threshold, 31 mV. The calibration and acceptance criteria are the same as those for the plasma assay.
Statistical Methods
Summary descriptive statistics for the PK parameter estimates were calculated to describe the characteristics of hydroxyurea after a single oral dose in SCD patients with normal renal function and in SCD patients with mild, moderate, or severe renal impairment and those with ESRD (CLcr < 15 mL/min or on maintenance hemodialysis). Linear or exponential regression of the estimated individual apparent total body clearance (CLT/F) and the dose-normalized area under the plasma concentration versus time curve from time 0 to infinity (AUC
) from the current study on CLcr was conducted to generate trend lines. No statistical analysis was done on the safety data.
Pharmacokinetics
Plasma concentration versus time and urinary recovery profiles were analyzed by noncompartmental analysis using the MENU/PKMENU application and the Statistical Analysis System (SAS, Version 6.12) software package.14 The peak plasma concentration (Cmax) and the time to reach the peak concentration (tmax) were obtained from experimental observations. The area under the plasma concentration versus time curve from time 0 to the time of the last quantifiable concentration (AUC0-t) was determined by summing the areas from time 0 to the time of last quantifiable concentration, calculated by using trapezoidal and log-trapezoidal methods. The AUC was determined by summing the areas from hour 0 to the time of last quantifiable concentration, calculated by using trapezoidal and logtrapezoidal methods, and the extrapolated area. The extrapolated area was determined by dividing the last quantifiable concentration by the slope of the terminal log-linear phase. The first-order rate constant of decline (
) of hydroxyurea concentrations in the terminal phase of the plasma concentration versus time profile was estimated by log-linear regression, using no weighting factor, of at least 3 data points that yielded a minimum mean square error. The absolute value of was used to estimate the apparent terminal elimination half-life (t1/2) by t1/2 = ln2/. The CLT/F was calculated as dose divided by AUC.
The amount of hydroxyurea excreted in urine during each collection interval was calculated by multiplying the urinary concentration of hydroxyurea by the volume of urine collected over that interval. The total urinary recovery (UR) was calculated as the cumulative amount excreted over the 36 hours and expressed as a percentage of the administered dose (%UR). Renal clearance (CLR) was estimated by dividing UR0-t by AUC0-t.
To guide dosing recommendation in renal impairment, 2 historical studies were used to provide a basis for comparison and target exposure for normal renal function. These 2 studies had individual dose and exposure information. The exposure and clearance data from the 2 historical studies were pooled to generate the mean and standard deviation (SD) values.
In a study by Charache et al,15,16 27 patients with sickle cell anemia were initially treated with hydroxyurea at oral doses ranging from 10 to 20 mg/kg/day, which were incrementally increased by 5 mg/kg every 8 weeks. The starting dose was based on the AUC of hydroxyurea over a period of 6 hours following a nominal oral dose of 25 mg/kg. This AUC determination was repeated on 2 occasions, separated by at least 1 day. Blood samples for the AUC estimation were collected predose and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours postdose on each occasion. All patients in the study likely had normal renal function because the mean (SD) creatinine clearance (CLcr) value reported was 165 (95) mL/min.
In study T91-0118, the PK and bioavailability of oral and intravenous hydroxyurea were evaluated in a randomized, 2-period crossover design study.16 Twenty-two patients with refractory solid tumors received 2000 mg of hydroxyurea orally or by a 0.5-hour zero-order intravenous infusion on study day 1 of the first treatment cycle, followed by an oral dose of 80 mg/kg every 3 days for 3 weeks. After a 1-week washout, the patients started the second treatment cycle with a 2000-mg dose of hydroxyurea by the route alternate to that employed for the first treatment cycle, followed by the same oral dosing schedule used for the first treatment cycle. Serial blood samples for PK analyses were collected over a 24-hour period postdose on day 1 of the 2 treatment cycles. All patients in the study were assumed to have normal renal function because serum creatinine was 
1.5 mg/dL.
To make a comparison of exposure between the current and the 2 historical studies and to make dosing recommendation based on exposure to hydroxyurea, we normalized all individual AUC values to a dose of 1000 mg, assuming linear PK. The AUC of hydroxyurea from time 0 to 8 hours (AUC0-8) was reported for individual patients in both studies of Charache et al15 and T91-0118.16 Individual dose-normalized AUC0-8 values from the 2 studies were extrapolated to AUC by taking the quotient of AUC0-8 and 0.9, where 0.9 is the mean ratio of the AUC0-8 observed and the AUC extrapolated in the patients with normal renal function (CLcr 90 mL/min) in the current study (n = 6, mean [SD]: 0.88 [0.04]), as well as the mean ratio of the AUC0-8 observed and the AUC extrapolated in all the patients pooled across the studies of Charache et al and T91-0118 (n = 69, mean [SD]: 0.87 [0.10]). These dose-normalized estimated AUC were pooled to generate the mean and SD. The individual CLT/F was estimated by dividing dose with the AUC extrapolated. The mean (SD) value of pooled CLT/F was used in this investigation.
The estimated individual CLT/F and the dose-normalized AUC from the current study were plotted against CLcr. Linear or exponential regression was performed on the data to generate trend lines. The pooled mean and the pooled mean ± 1 SD values of AUC or CLT/F from the historical studies were superimposed on the same graph. The intersection of the trend line and the pooled mean + 1 SD line (AUC) or the pooled mean - 1 SD line (CLT/F) was used to guide the dose recommendation based on CLcr. Pooled historical data were used because these patients had normal renal function, and there was excellent agreement between the AUC and CLT/F values in SCD patients with normal renal function from the current study and the pooled historical data.
Pharmacokinetic modeling and simulation were also used in the analyses. Individual plasma concentration versus time data were subject to compartmental model fitting using WinNonlin software.17 The selection of the model (1- vs 2-compartment) was determined by goodness of fit based on lower values of the Akaike information criterion (AIC), Schwartz criterion (SC), and the coefficient of determination (R2). For patients whose plasma concentration-time profiles fit to a 1-compartment model (model 4, first-order absorption, with lag time, first-order elimination), the parameters estimated were V/F (apparent volume of distribution), K01 (absorption rate constant), K10 (elimination rate constant), and tlag (absorption lag time). For those patients whose plasma concentration versus time profiles fit to a 2-compartment model (macro-constant, first-order absorption, first-order elimination, with lag time [model 14] or without lag time [model 13]), the parameters estimated were A (zero time intercept associated with the alpha phase), B (zero time intercept associated with the beta phase), K01 (absorption rate constant), 
(macro-rate constant associated with the distribution phase), ß (macro-rate constant associated with the elimination phase), and tlag (absorption lag time [model 14]). Due to missing plasma data (0.5-2.0 hours) in 1 patient (001-09) with normal renal function, PK modeling and simulation was not done for that patient.
Assuming linear kinetics, the individual hydroxyurea plasma concentration-time data were simulated after multiple dosing (qd x 3) using WinNonlin software with the model parameters generated. Because of the short half-life of hydroxyurea, steady state is assumed by the third day of dosing. In these simulations, the multiple-dosing regimen was 15 mg/kg qd or 7.5 mg/kg qd for those patients who needed dose modification. Individual doses were calculated based on body weight and rounded for use in the simulation as per the protocol (ie, those with the last 2 integers of 1-50 were rounded down, and those with the last 2 integers of 51-99 were rounded up). Trough hydroxyurea levels were examined to confirm steady-state conditions. Steady-state Cmax and AUC in 1 dosing interval, AUC0-24, were determined or calculated by noncompartmental method using day 3 concentration-time data generated by simulation.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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90 mL/min), 2 patients had mild renal impairment (CLcr = 60-89 mL/min), 3 patients had moderate renal impairment (CLcr = 30-59 mL/min), 2 patients had severe renal impairment (CLcr = 15-29 mL/min), and 3 patients had ESRD (CLcr < 15 mL/min), with 2 of them on maintenance hemodialysis. The patient demographic data are listed in Table I.
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Safety
Eight of the 17 (47%) patients who received study medication experienced a total of 11 treatment-emergent adverse events (AEs), including 1 serious adverse event (SAE) and 10 nonserious AEs. The SAE (worsening renal failure in 1 patient [001-10] with severe renal impairment) was very severe. This patient died 16 days after the administration of study medication. However, the causality of this SAE was assessed to be unrelated to the study medication. The other 10 AEs were moderate or mild and were also reported as unrelated to the study medication. The only event reported by more than 1 patient was nausea (2 patients). There was no patient discontinuation for any reasons in the study.
Noncompartmental Analysis
The profiles of mean (SD) plasma concentrations of hydroxyurea versus time in the SCD patients with selected degree of renal impairment are depicted in Figure 1. A summary of the mean PK parameter values is provided in Table II. Due to missing plasma data (0.5-2.0 hours) in 1 patient (001-09) with normal renal function, only t1/2 and %UR were reported for that patient. As the degree of renal impairment worsened, the systemic exposure to hydroxyurea increased, and the urinary recovery decreased. The mean AUC was increased by 88%, 70%, 62%, 80%, and 152% for patients with mild, moderate, severe renal function impairment, and ESRD with and without hemodialysis, respectively, compared to patients with normal renal function. The changes in CLT/F, CLR, and t1/2 were also generally in keeping with this trend (ie, higher exposure, lower clearance, and longer half-life). There was no apparent trend between Cmax or tmax and CLcr.It appeared that hemodialysis played a significant role in the elimination of the drug in the ESRD patients, as exposure was reduced by 33% compared to the exposure in the absence of hemodialysis.
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Dose Normalization and Pooling of the Historical Data
Table III displays the dose-normalized (1000 mg) individual AUC and CLT/F values for the current study. The mean (SD) values of the pooled dose-normalized AUC and CLT/F from the 2 historical studies (n = 69) are 89 (38) µg•h/mL and 216 (76) mL/min, respectively.
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Dosing Recommendation
The plots of individual dose-normalized AUC versus CLcr and CLT/F versus CLcr from the current study are displayed in Figures 2 and 3, respectively. Superimposed on these plots are the pooled mean and the pooled mean ± 1 SD from the historical studies. Based on the intersection of the trend line and the pooled mean + or - SD line, both figures suggested that the CLcr cutoff for dose modification was approximately 30 to 40 mL/min. However, values for 2 patients in the group of CLcr > 30-40 mL/min were outside the range of the mean ± SD of the historical AUC values, whereas values for 3 patients in the group of CLcr > 30-40 mL/min were outside the range of the mean ± SD of the historical CLT/F values. Accordingly, the CLcr cutoff was moved to 60 mL/min to account for intersubject variability in hydroxyurea exposure and in consideration of the use of dose titration in clinical practice. Figure 2 suggests that most of the AUC values in patients with CLcr 60 mL/min in the current study are within the variability observed in the historical data from patients with normal renal function. This observation supports the use of the CLcr cutoff of 60 mL/min for dose modification. The relationship between CLT/F and CLcr also supports this contention. Based on the latter, the patients in the current study were divided into 2 groups: CLcr 60 mL/min (group 1) and <60 mL/min or ESRD (group 2). The individual and mean (SD) AUC values for patients in group 1 and group 2 are shown in Table IV and depicted in Figure 4.
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The results indicate that the mean exposure (AUC) for group 2 patients is approximately 51% higher when compared to the group 1 mean value, suggesting that a 50% dose reduction may be appropriate for group 2 patients. After a 50% dose reduction for patients with CLcr < 60 mL/min or ESRD, the mean AUC is below the mean value of patients with CLcr 60 mL/min. However, the mean ± SD is well within the range of the mean ± SD of the historical AUC data, as shown in Figure 4. Despite the limited data, these results suggest that in sickle cell anemia patients with CLcr < 60 mL/min or ESRD, the initial daily dose of hydroxyurea should be modified from 15 to 7.5 mg/kg. On dialysis days, hydroxyurea should be administered to ESRD patients following hemodialysis.
Pharmacokinetic Modeling and Simulation
Individual PK models with weighting factors are listed in Table V. Simulated steady-state hydroxyurea exposure data are listed in the same table. As the data indicated, although the mean AUC0-24 of the 7.5-mg/kg dose for patients with CLcr < 60 mL/min is lower than that of the 15-mg/kg dose for patients with CLcr 60 mL/min, the mean ± SD value (80.41 ± 24.58) is contained in the range of the historical AUC data, 89 ± 38 µg•h/mL, mentioned in the previous result section.
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DISCUSSION |
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There have been previous publications on the clinical PK of hydroxyurea. Bioavailability of hydroxyurea following oral administration was found to be 79% to 108% in patients with cancer.12,18 The findings are consistent with those from other studies in cancer patients, in which plasma hydroxyurea concentrations were comparable following chronic intravenous and oral administration.19,20 The volume of distribution of hydroxyurea in humans has been estimated to be approximately equal to total body water.18 It is also estimated that hydroxyurea is 75% to 80% bound to serum proteins.21 The elimination of hydroxyurea consists of both metabolism and renal excretion.22 The urinary recovery of hydroxyurea as unchanged drug is reported to be approximately 35% of orally administered dose in patients with normal renal function.12 In patients with cancer, hydroxyurea renal clearance has been reported to be 75% of the glomerular filtration rate.18 These findings are consistent with the results of the current study.
It has been reported that there is a nonlinear relationship between plasma hydroxyurea concentrations and dose in human clinical trials. Beckloff et al21 reported plasma hydroxyurea concentrations following both oral doses of 20 and 80 mg/kg. More recently, Charache et al15 reported plasma concentrations in patients with sickle cell anemia receiving oral doses ranging from 10 to 35 mg/kg. The regression line between dose and plasma concentration demonstrated that the relationship was curvilinear, concave up. As renal clearance with glomerular filtration was deemed linear with dose, the nonlinear PK was assumed to be attributable to a saturable metabolic capacity.22
Although nonlinear PK of hydroxyurea was found for the dose range mentioned above, 2 recent studies using relatively low dosages of hydroxyurea demonstrated apparent linear PK. Villani et al23 administered oral doses of hydroxyurea 500 mg every 12 hours for 4 weeks to 9 patients with HIV infection. Serum hydroxyurea was measured between 1 and 4 weeks of the study. The PK fit well with a linear, 1-compartment model. Newman et al24 administered hydroxyurea by continuous infusion for 120 hours at 3 dosage levels (1.0, 2.0, and 3.2 g/m2/day). There appeared to be a linear relationship between the average steady-state hydroxyurea plasma concentrations (93, 230, and 302 µmol/L, respectively) and the infusion rate. Garcia et al25 also reported a linear relationship between the average steady-state hydroxyurea exposure levels (plasma and peritoneal fluid concentrations) and hydroxyurea dose levels (2.0, 2.5, 3.0, and 3.6 g/m2/day) after a 72-hour infusion in 28 cancer patients. These results of linear PK are consistent with the fact that in the study by Charache et al,15 the regression line between dose and plasma concentration appeared to be linear in the low-dose range (±15 mg/kg), although it looked curvilinear in the upper range.
Based on these literature reports, hydroxyurea might present nonlinear PK after administration of a relatively high dosage. In the current study, hydroxyurea dose of 15 mg/kg and our recommended initial dose (7.5 mg/kg) for SCD patients with renal insufficiency (CLcr < 60 mL/min) fall within the low hydroxyurea dose range that is supposed to render linear PK. Furthermore, Dover et al26 have reported a significant correlation between serum creatinine and hydroxyurea plasma levels in patients with sickle cell anemia. This further supports the approach taken in the current study (ie, hydroxyurea dose modification for SCD patients with renal insufficiency would be based on the degree of renal impairment).
In summary, the PK results from the current study indicate that the systemic exposure to hydroxyurea is correlated to renal function, and hence a dose reduction in patients with renal insufficiency is recommended. The dose recommendation is based on a comparison between the predicted exposure at a reduced dose in patients with CLcr < 60 mL/min and the historical exposure data in patients with normal renal function. Pharmacokinetic modeling and simulation were also conducted in the current study to compare the results with those of the alternate approach. Although the patient numbers in each renal function arm are limited due to tremendous enrollment challenge, the data reveal an apparent trend regarding the effect of renal impairment on both the systemic exposure and the urinary recovery of hydroxyurea. Based on the findings, the FDA approved the dose recommendation of hydroxyurea in SCD patients with renal insufficiency (CLcr < 60 mL/min) in July 2003. This recommended dose (7.5 mg/kg/day) of hydroxyurea is anticipated to provide a safe initial dose regimen in treating SCD in patients with renal impairment.
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ACKNOWLEDGEMENTS |
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REFERENCES |
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1. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. 1997;337: 762-769.
2. Steinberg MH. Management of sickle cell disease. N Engl J Med. 1999;340: 1021-1030.
3. Hebbel RP, Boogaerts MAB, Eaton JW, Steinberg MH. Erythrocyte adherence to endothelium in sickle cell anemia: a possible determinant of disease severity. N Engl J Med. 1980;302: 992-995.[Abstract]
4. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease: rates and risk factors. N Engl J Med. 1991;325: 11-16.[Abstract]
5. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease: life expectancy and risk factors for early death. N Engl J Med. 1994;330: 1639-1644.
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