Don't Do Different Things Do Things Differently! Drug Development in Rare Diseases.

Although definitions of rare disease vary, most acknowledge that there are small numbers of affected patients compared with other conditions. Small numbers of patients, overlapping involvement of investigators as researchers and caregivers, as well as close relationships between researchers and manufacturers require a different pattern of drug development. Regulatory guidances for rare diseases are available, as well as ones for specific rare diseases. Maintaining drug supply for rare diseases also demands innovative approaches.

Population pharmacokinetic modelling of factor IX activity after administration of recombinant factor IX in patients with haemophilia B.

PURPOSE: The aim is to develop a pharmacokinetic model for factor IX activity (FIX) after BeneFIX (nonacog alfa, rFIX) administration and assess potential covariates using all available clinical data collected during development. METHODS: The data set for model development combined observations from eight studies. Postdose FIX observations were adjusted by subtracting predose FIX if these were above the lower limit of quantification (BLQ) and all BLQ observations were removed. A population pharmacokinetic model was then developed with 4936 observations from 201 patients. Two additional studies (385 observations from 72 patients) became available and were used to evaluate the model. RESULTS: A two-compartment model, parameterized for clearance (CL), volume of distribution of the central (V1) and peripheral (V2) compartments, and intercompartmental clearance (Q), with an effect of weight on all parameters was the final model. Weight was incorporated as a power function with exponent estimates close to conventional allometric scaling. Including interoccasion variability (IOV) on CL and V1 showed decreases in the objective function. Investigations of a full block omega matrix lead to the retention of a correlation between V2 and Q. Age was not a significant covariate with weight already included in the model. Observations in the studies used for evaluation were found to be higher than simulated values immediately after dosing, as well as a week after dosing. The differences may be due perhaps to differences in the patients enrolled in the evaluation studies (all were adults) as well as the sample collection time after dosing (longer after dosing in the evaluation studies). CONCLUSIONS: FIX is appropriately modelled as a two-compartment model after rFIX administration. When weight is included, no additional effect of age is observed. Longer times of observation after dosing may be helpful in refining the model.

Industry Perspective of Drug Development for Pregnant/Breastfeeding Women.

As part of drug development, drug companies conduct experiments to gather data about the potential toxicity of medications in pregnant and lactating animals. Increasingly, physiologically based pharmacokinetic models are developed to simulate drug concentrations in pregnant and lactating women. As these women are not usually included in clinical trials, targeted postapproval safety monitoring, registries, or clinical studies may be performed to gather safety and efficacy information about drug use in these special populations.

Multicentre, randomized, open-label study of on-demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects.

Few randomized studies have reported on the use of factor IX (FIX) for secondary prophylaxis in haemophilia B patients. This study aimed to evaluate the efficacy and safety of two secondary prophylaxis regimens of recombinant coagulation FIX, nonacog alfa, compared with on-demand therapy. Male subjects aged 6-65 years with severe or moderately severe haemophilia B (FIX:C ≤ 2, n = 50) and ≥12 bleeding episodes (including ≥6 haemarthroses episodes) within 12 months of study participation were enrolled in this multicentre, randomized, open-label, four-period crossover trial. The primary measure was the annualized bleeding rate (ABR) of two prophylactic regimens vs. on-demand therapy. In the intent-to-treat group, mean ABR values were 35.1, 2.6 and 4.6 for the first on-demand period, the 50 IU kg(-1) twice-weekly period, and the 100 IU kg(-1) once-weekly period respectively. Differences in ABR between the first on-demand period and both prophylaxis regimens were significant (P < 0.0001); no significant differences were observed between prophylaxis regimens (P = 0.22). Seven serious adverse events occurred in five subjects, none related to study drug. Results demonstrated that secondary prophylaxis therapy with nonacog alfa 50 IU kg(-1) twice weekly or 100 IU kg(-1) once weekly reduced ABR by 89.4% relative to on-demand treatment. Both prophylaxis regimens demonstrated favourable safety profiles in subjects with haemophilia B.

Impact of different factors on the probability of clinical response in tigecycline-treated patients with intra-abdominal infections.

Patients with intra-abdominal infections differ with regard to the type of infection and the severity of illness. However, the impact of these factors, together with differences in drug exposure, on clinical response is not well understood. Using phase 2 and 3 data for patients with complicated intra-abdominal infections, the relative importance of tigecycline exposure, host factors, and disease factors, alone or in combination, for the probability of clinical response was examined. Patients with complicated intra-abdominal infections who received tigecycline intravenously as a 100-mg loading dose followed by 50 mg every 12 h for 5 to 14 days and who had adequate clinical, pharmacokinetic, and response data were evaluated. Multivariable logistic regression was used to identify factors associated with clinical response. A final multivariable logistic regression model demonstrated six factors based on 123 patients to be predictive of clinical success: a weight of <94 kg (P = 0.026), the absence of Pseudomonas aeruginosa in baseline cultures (P = 0.021), an APACHE II score of <13 (P = 0.029), non-Hispanic race (P = 0.005), complicated appendicitis or cholecystitis (P = 0.004), and a ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) of > or =3.1 (P = 0.003). The average model-predicted probability of clinical success when one unfavorable factor was present was 0.940. This probability was lower (0.855) when the AUC/MIC ratio was < 3.1 and the remaining five factors were set to the favorable condition. The average model-predicted probability of clinical success in the presence of two unfavorable factors was 0.594. These findings demonstrated the impact of individual and multiple factors on clinical response in the context of drug exposure.

Population pharmacokinetics of tigecycline in healthy volunteers.

Tigecycline, a novel glycylcycline, possesses broad-spectrum antimicrobial activity. A structural population pharmacokinetic model for tigecycline was developed based on data pooled from 5 phase I studies. Intravenous tigecycline was administered as single (12.5-300 mg) or multiple (25-100 mg) doses every 12 hours for up to 10 days. Three-compartment models with zero-order input and first-order elimination separately described the single- or multiple-dose full-profile data. Additional models were evaluated using a subset of the phase I data mimicking the phase II/III trial sparse-sampling scheme and dosage. A 2-compartment model best described the reduced phase I data following single or multiple doses and provided reliably accurate estimates of tigecycline AUC(0-12). This modeling supported phase II/III population pharmacokinetic model development to further determine individual patient tigecycline exposures for safety and efficacy analyses.

Population pharmacokinetics of tigecycline in patients with complicated intra-abdominal or skin and skin structure infections.

Tigecycline, a first-in-class expanded glycylcycline antimicrobial agent, has demonstrated efficacy in the treatment of complicated skin and skin structure infections (cSSSI) and complicated intra-abdominal (cIAI) infections. A population pharmacokinetic (PK) model for tigecycline was developed for patients with cSSSI or cIAI enrolled in two phase 2 clinical trials, and the influence of selected demographic factors and clinical laboratory measures was investigated. Tigecycline was administered as an intravenous loading dose followed by a 0.5- or 1-h infusion every 12 h for up to 14 days. Blood samples were collected the day before or the day of hospital discharge for the determination of serum tigecycline concentrations. Patient covariates were evaluated using stepwise forward (alpha = 0.05) and backward (alpha = 0.001) procedures. The predictive performance of the model was assessed separately using pooled data from either two phase 3 studies for patients with cSSSI or two phase 3 studies for patients with cIAI. A two-compartment model with zero-order input and first-order elimination adequately described the steady-state tigecycline concentration-time data. Tigecycline clearance was shown to increase with increasing weight, increasing creatinine clearance, and male gender (P < 0.001). The final model provided a relatively unbiased fit to each data set. Individual predicted values of the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) were generally unbiased (median prediction error, -1.60% to -3.78%) and were similarly precise (median absolute prediction error, <4%) when compared across data sets. The population PK model provided the basis to obtain individual estimates of steady-state AUC(0-12) in later exposure-response analyses of tigecycline safety and efficacy in patients with cSSSI or cIAI.

Impact of age and gender on the pharmacokinetics of gemtuzumab ozogamicin.

STUDY OBJECTIVE: To determine the pharmacokinetic parameters of the components of gemtuzumab ozogamicin and to assess the possible influence of age and gender on the values. DESIGN: Phase II, multicenter, open-label, nonrandomized, parallel study SETTING: Hospitals and outpatient oncology clinics. PATIENTS: Fifty-eight patients with acute myeloid leukemia in first relapse participated. Demographic data included 29 men and 29 women; 34 were younger than 60 years of age (mean age 53+/-16 yrs). INTERVENTION: Patients received gemtuzumab ozogamicin as a single 2-hour infusion of 9 mg/m2. Serial plasma samples were collected over 10 days after the beginning of the infusion. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of components of gemtuzumab ozogamicin (hP67.6 antibody, total and unconjugated calicheamicin derivatives) were measured by validated enzyme-linked immunosorbent assays. Pharmacokinetic parameters were determined by noncompartmental methods and comparisons between groups were made by analysis of variance. No significant differences were seen between men and women or between those over 60 and those less than 60 years of age in maximum concentration, time to maximum concentration, area under the curve, clearance, or volume of distribution for components of gemtuzumab ozogamicin. CONCLUSION: No differences occur in the pharmacokinetics of the components of gemtuzumab ozogamicin (hP67.6 or calicheamicin) based on gender or age.

The pharmacokinetics of etanercept in healthy volunteers.

OBJECTIVE: To describe the pharmacokinetics of etanercept when administered by subcutaneous injection in single doses to healthy volunteers. METHODS: Twenty-six healthy volunteers between 19 and 50 years of age received single doses of etanercept 25 mg by subcutaneous injection into the abdomen. Serial serum samples were collected for 21 days. An enzyme-linked immunosorbent assay with a quantitation limit of 0.3 ng/mL was used to measure the drug concentrations. RESULTS: Etanercept was well tolerated by healthy volunteers. A one-compartment model was found to best describe the concentration-time data and was used to determine the pharmacokinetic parameters. Etanercept is slowly absorbed from the site of injection with a time of peak concentration (+/- SD) of 51 +/- 14 hours; peak concentration was 1.46 +/- 0.72 mg/L. The AUC was 235 +/-98 mg x h/L, apparent clearance was 132 +/- 85 mL/h, apparent volume of distribution was 12 +/- 6 L, and the half-life was 68 +/- 19 hours. CONCLUSIONS: Etanercept was slowly absorbed and slowly eliminated after subcutaneous administration. Dosing at the recommended rate of 25 mg twice weekly would be expected to result in concentrations of approximately 3 mg/L. Intersubject variability for apparent clearance in healthy volunteers was 64%.

Chiral bioequivalence: effect of absorption rate on racemic etodolac.

BACKGROUND: For many racemic drugs, bioequivalence assessment based on isomer-nonspecific assays is appropriate because enantiomeric area under the concentration-time curve (AUC) exposure ratios are close to unity. Use of nonspecific methods in cases in which the ratio is substantially greater or less than 1, however, may obscure real therapeutic differences among formulations, especially if the enantiomers exhibit differing pharmacological potencies. OBJECTIVE: To examine the influence of absorption rate on etodolac bioequivalence as measured by total [(R,S)-] and (S)-etodolac. DESIGN: Single dose, 3-period, crossover, pharmacokinetic study in 24 healthy volunteers in which the administration rate of etodolac was varied. METHODS: Participants received etodolac 400mg in solution, given as a single dose over 1 minute or as divided doses over 30 and 90 minutes. Unresolved and enantiomer concentrations of etodolac were measured by a validated HPLC assay. The enantiomer ratio was similarly measured by HPLC. RESULTS: Bioequivalence parameters derived for both unresolved and (S)etodolac indicate that peak plasma drug concentration (Cmax) was not bioequivalent. By delaying absorption, bioequivalence was lost. CONCLUSIONS: Collectively, these data demonstrate that bioequivalence between 2 products of etodolac based on enantiomerically nonspecific criteria alone may not generalise to the pharmacologically relevant (S)-enantiomer. This suggests that enantiospecific assays are necessary for bioequivalence assessments.

Pharmacokinetics of etodolac in patients with stable juvenile rheumatoid arthritis.

This was a single-center, open-label, single-dose pharmacokinetic study of etodolac in pediatric and adolescent patients with stable juvenile rheumatoid arthritis (JRA). Eleven male and female patients with JRA (8.1 to 14.8 years of age, weighing 26.4 to 59.5 kg) received a single oral dose of etodolac (200, 300, or 400 mg based on body weight). Clinical laboratory measurements, measurement of vital signs, and physical examinations were performed to monitor safety. Concentrations of etodolac were determined in plasma using high-performance liquid chromatography with ultraviolet detection with a limit of quantitation of 0.2 mg/L and were analyzed using a noncompartmental pharmacokinetic method. Pharmacokinetic parameters observed were consistent in magnitude and degree of variability with data from healthy adult subjects receiving a single 400- or 600-mg dose of etodolac. Although the mean fraction of unbound drug in patients with JRA was higher than in healthy adults, the oral clearance was independent of age. No serious adverse events occurred during this study. Etodolac yielded consistent pharmacokinetic values among stratified dose subgroups. Single doses of all etodolac treatments were well tolerated in both pediatric and adolescent patients.

The influence of bromfenac on the pharmacokinetics and pharmacodynamic responses to glyburide in diabetic subjects.

STUDY OBJECTIVE: To assess the effect of bromfenac sodium, a nonnarcotic analgesic drug under development, on the pharmacokinetics and pharmacodynamics of glyburide in patients with type II diabetes. DESIGN: Randomized, double-blind, placebo-controlled, multiple-dose study with a two-period crossover design. PATIENTS: Eleven men and one woman (age 36-64 yrs) whose diabetes was responsive to oral sulfonylurea therapy. INTERVENTIONS: Placebo or bromfenac 50 mg was given as a single oral dose 3 times/day for the first 3 days of the study. On days 4-6, patients received the alternative treatment. For at least 3 months before and during the study, patients took their usual single daily dose of glyburide 10 mg. MEASUREMENTS AND MAIN RESULTS: Bromfenac concentrations were measured by high-performance liquid chromatography with ultraviolet detection. Glyburide concentrations were measured by gas chromatography with nitrogen-phosphorus detection. Glycemia was measured repeatedly on day 3 of each treatment. Pharmacokinetic analysis was performed with noncompartmental techniques. No significant differences in the pharmacokinetics of glyburide or in the pharmacodynamic response of serum glucose levels were observed between placebo and bromfenac. Intersubject variability of concentrations was modest for glyburide and glucose, with a CV of 43% or less. CONCLUSION: Glyburide levels are not changed during concomitant administration of bromfenac.

Absolute bioavailability of bromfenac in humans.

OBJECTIVE: To estimate absolute bioavailability of bromfenac and to compare its pharmacokinetics after intravenous and oral administration. DESIGN: This was a randomized, open-label, single-dose, crossover study conducted under fasting conditions with a washout period of at least 48 hours between doses. Each subject received a 50-mg dose of bromfenac both intravenously and orally followed by collection of blood samples at specified time intervals. Bromfenac plasma concentrations were measured by using a validated HPLC method with ultraviolet detection. SETTING: The study was conducted at the Drug Evaluation Unit. Hennepin County Medical Center, Minneapolis, MN. SUBJECTS: The participants consisted of 12 healthy subjects between 18 and 45 years of age and within +/-15% of ideal body weight. RESULTS: The mean +/- SD absolute bioavailability of bromfenac was 67% +/- 20%. CONCLUSIONS: The pharmacokinetic parameters of bromfenac were similar after intravenous and oral administration, suggesting that the prototype oral dosage form is optimal and that the observed intersubject variability is due to bromfenac itself, not the type of dosage form.

Effects of age and gender on the pharmacokinetics of bromfenac in healthy volunteers.

OBJECTIVE: To compare the pharmacokinetic parameters of bromfenac, a nonsteroidal antiinflammatory drug under development, in healthy volunteers of various ages and either gender, after single and multiple doses. DESIGN: Open-label, single- and multiple-dose, nonrandomized, parallel study. PARTICIPANTS: Twenty young (18-45 y), 12 young-elderly (65-74 y), and 12 elderly (75-85 y) subjects were studied. Half of the subjects in each group were women. INTERVENTIONS: Bromfenac was given as a single 50-mg dose and then as 50-mg doses every 12 hours for 3 additional days. Twelve blood samples were collected for 12 hours after the first and last doses. MAIN OUTCOME MEASURES: Bromfenac concentrations were measured by using an HPLC procedure with ultraviolet detection. Unbound bromfenac concentrations were measured by equilibrium dialysis. Pharmacokinetic analysis was performed by noncompartmental techniques. RESULTS: No significant differences related to gender were detected. Significant differences were observed in half-life (t1/2), AUC, clearance, and apparent volume of distribution when the elderly group was compared with the young group and in t1/2 when the elderly group was compared with the young-elderly group, although substantial overlap among groups was observed. CONCLUSIONS: Administration of bromfenac to young-elderly or elderly subjects of either gender does not require a dosage adjustment in acute settings. Consideration should be made to titrating dosages in patients over 75 years of age who require repeated doses.

Evaluation of pharmacokinetic interaction between bromfenac and phenytoin in healthy males.

An open-label, nonrandomized, multiple-dose, inpatient study was conducted in healthy male volunteers to compare the pharmacokinetics of bromfenac and phenytoin when the drugs are given individually and concomitantly. Twelve men received multiple oral doses of bromfenac for 4 days and then oral phenytoin for up to 14 days followed by concomitant administration of bromfenac and phenytoin for 8 days. Concomitant administration of the two drugs caused an approximate 40% decrease in the mean peak plasma concentration (Cmax) and the interdose area under the concentration-time curve (AUC) of bromfenac. The oral clearance (Clpo) of bromfenac doubled and the volume of distribution increased by 77%. For phenytoin, the mean peak serum concentration and the AUC increased by 9% and 11%, respectively, in the presence of bromfenac. The only change in unbound phenytoin was a 16% increase in the AUC. Although statistically significant, the changes in the pharmacokinetic parameters of phenytoin and unbound phenytoin were small. Adjustments in the dose of phenytoin should not be required during concomitant administration of bromfenac, although each patient's clinical status should be evaluated individually.

Population pharmacokinetics of intravenous amiodarone in patients with refractory ventricular tachycardia/fibrillation.

A population approach was used to determine the pharmacokinetics of amiodarone in 245 patients receiving intravenous amiodarone for the short-term treatment of refractory, hemodynamically destabilizing, ventricular tachycardia and/or fibrillation. A two-compartment model employing proportional statistical models to estimate intersubject variability and an additive-proportional model to estimate residual error were found to best describe the data. The mean (% coefficient of variation, CV) value for clearance was 0.22 L/hr/kg (13%), central volume of distribution was 0.30 L/kg (11%), peripheral volume of distribution was 10.0 L/kg (9.5%), and intercompartmental clearance was 0.71 L/hr/kg (16%). The mean (%CV) intersubject variance estimates were 1.52 (31%) for clearance, 0.37 (46%) for central volume, 0.37 (67%) for peripheral volume, and 0.44 (39%) for intercompartmental clearance. The estimate of residual error (%CV) was 0.53 (13%). Age, gender, height, serum creatinine concentration, serum alkaline phosphatase activity, ejection fraction, and therapeutic response to treatment did not contribute to the variability in patient pharmacokinetics. It was concluded that the pharmacokinetic parameters of amiodarone in these patients were similar to those reported for healthy volunteers and were similarly variable. Estimates of pharmacokinetic parameters made during short periods of observation may not be entirely consistent with parameters estimated during prolonged periods of observation of healthy volunteers who receive single doses.

Lack of interaction between bromfenac and methotrexate in patients with rheumatoid arthritis.

OBJECTIVE: To compare the pharmacokinetics of methotrexate (MTX) and bromfenac administered separately or coadministered in patients with rheumatoid arthritis (RA). METHODS: Patients received their usual weekly oral dose of MTX on Days 1 and 8 and bromfenac 50 mg every 8 h from Days 4 to 9. On Days 1 and 8 serial blood and urine samples were collected to study the pharmacokinetics of MTX and 7-hydroxymethotrexate (7-OHMTX). Bromfenac pharmacokinetics were studied on Days 7 and 8. Concentrations of the analytes were assayed using validated high performance liquid chromatography methods. RESULTS: Nine patients, 5 women and 4 men, completed the study. No statistically significant changes were observed in any of the pharmacokinetic variables evaluated for bromfenac with or without MTX. Bromfenac also did not alter the pharmacokinetics of low dose MTX. However, some significant changes were observed in the pharmacokinetics of 7-hydroxymethotrexate: a 30% increase in dose normalized area under the serum concentration time curve (mean +/- SD) to 3102 +/- 1397 micrograms.h/l and a 16% decrease in renal clearance to 10.0 +/- 6.7 ml/h/kg. Eight patients had mild or moderate adverse events: most were considered unrelated to the study drug by the investigator. One patient did not complete the study because of moderate hypertension. No patient had clinically important abnormal laboratory test results. CONCLUSION: No clinically significant changes in MTX pharmacokinetics were detected in patients with RA when bromfenac was added to MTX therapy. Although 7-OHMTX concentrations were elevated, the changes were small and unlikely to be of clinical significance. MTX did not alter the pharmacokinetics of bromfenac.

A pharmacokinetic primer for intravenous nurses.

Traditionally, drug doses and intervals between doses have been empirically decided by prescribers. Doses and intervals were subsequently adjusted based on observed efficacy or toxic effects. In the absence of consistent clinical findings or when the disease being treated is episodic in nature, such as in the case of asthma or epilepsy, optimal dosing is difficult to achieve. An alternative approach is the adjustment of doses based on the concentration of drugs in plasma. This approach has come to be called therapeutic drug monitoring, or TDM. To make adjustment of doses more efficient, mathematical models have been developed that describe and predict drug concentrations in various body fluids. These mathematical models incorporate pharmacokinetic parameters, such as volume of distribution, absorption rate constant, and clearance, which, when known for a particular patient or group of patients, allow judicious adjustment of doses of drugs that might otherwise be ineffective. This article reviews the model most commonly used in TDM and explains the parameters associated with it. It also considers the importance of TDM in clinical practice and the role of the nurse in this aspect of patient care.