Parameter Estimation and Reporting in Noncompartmental Analysis of Clinical Pharmacokinetic Data.

The noncompartmental analysis (NCA) of pharmacokinetic (PK) data is important throughout all phases of clinical drug development. Although there are numerous regulatory guidances and articles in the literature concerned with best practices for the modeling of PK data, there are relatively few sources of information on how to conduct a high-quality NCA. This article provides a systematic review of issues related to the estimation of plasma and urine PK parameters with the intent of encouraging rigor in the performance of NCAs so as to provide reliable and informative analysis results.

Criteria for reporting noncompartmental estimates of half-life and area under the curve extrapolated to infinity.

Various criteria have been proposed for determining the reliability of noncompartmental pharmacokinetic estimates of the terminal disposition phase half-life (t1/2 ) and the extrapolated area under the curve (AUCextrap ). This simulation study assessed the performance of two frequently used reportability rules: the terminal disposition phase regression adjusted-r2 classification rule and the regression data point time span classification rule. Using simulated data, these rules were assessed in relation to the magnitude of the variability in the terminal disposition phase slope, the length of the terminal disposition phase captured in the concentration-time profile (data span), the number of data points present in the terminal disposition phase, and the type and level of variability in concentration measurement. The accuracy of estimating t1/2 was satisfactory for data spans of 1.5 and longer, given low measurement variability; and for spans of 2.5 and longer, given high measurement variability. Satisfactory accuracy in estimating AUCextrap was only achieved with low measurement variability and spans of 2.5 and longer. Neither of the classification rules improved the identification of accurate t1/2 and AUCextrap estimates. Based on the findings of this study, a strategy is proposed for determining the reportability of estimates of t1/2 and area under the curve extrapolated to infinity.

Performance characteristics of the adjusted r2 algorithm for determining the start of the terminal disposition phase and comparison with a simple r2 algorithm and a visual inspection method.

The adjusted r2 algorithm is a popular automated method for selecting the start time of the terminal disposition phase (tz ) when conducting a noncompartmental pharmacokinetic data analysis. Using simulated data, the performance of the algorithm was assessed in relation to the ratio of the slopes of the preterminal and terminal disposition phases, the point of intercept of the terminal disposition phase with the preterminal disposition phase, the length of the terminal disposition phase captured in the concentration-time profile, the number of data points present in the terminal disposition phase, and the level of variability in concentration measurement. The adjusted r2 algorithm was unable to identify tz accurately when there were more than three data points present in a profile's terminal disposition phase. The terminal disposition phase rate constant (λz ) calculated based on the value of tz selected by the algorithm had a positive bias in all simulation data conditions. Tolerable levels of bias (median bias less than 5%) were achieved under conditions of low measurement variability. When measurement variability was high, tolerable levels of bias were attained only when the terminal phase time span was 4 multiples of t1/2 or longer. A comparison of the performance of the adjusted r2 algorithm, a simple r2 algorithm, and tz selection by visual inspection was conducted using a subset of the simulation data. In the comparison, the simple r2 algorithm performed as well as the adjusted r2 algorithm and the visual inspection method outperformed both algorithms. Recommendations concerning the use of the various tz selection methods are presented.

Phase 1 dose-escalation, pharmacokinetic, and cerebrospinal fluid distribution study of TAK-285, an investigational inhibitor of EGFR and HER2.

INTRODUCTION: This phase 1 study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, cerebrospinal fluid (CSF) distribution, and preliminary clinical activity of the receptor tyrosine kinase inhibitor TAK-285. METHODS: Patients with advanced, histologically confirmed solid tumors and Eastern Cooperative Oncology Group performance status ≤2 received daily oral TAK-285; daily dose was escalated within defined cohorts until MTD and recommended phase 2 dose (RP2D) were determined. Eleven patients were enrolled into an RP2D cohort. Blood samples were collected from all cohorts; CSF was collected at pharmacokinetic steady-state from RP2D patients. Tumor responses were assessed every 8 weeks per Response Evaluation Criteria in Solid Tumors. RESULTS: Fifty-four patients were enrolled (median age 60; range, 35-76 years). The most common diagnoses were cancers of the colon (28 %), breast (17 %), and pancreas (9 %). Escalation cohorts evaluated doses from 50 mg daily to 500 mg twice daily; the MTD/RP2D was 400 mg twice daily. Dose-limiting toxicities included diarrhea, hypokalemia, and fatigue. Drug absorption was fast (median time of maximum concentration was 2-3 h), and mean half-life was 9 h. Steady-state average unbound CSF concentration (geometric mean 1.54 [range, 0.51-4.27] ng/mL; n = 5) at the RP2D was below the 50 % inhibitory concentration (9.3 ng/mL) for inhibition of tyrosine kinase activity in cells expressing recombinant HER2. Best response was stable disease (12 weeks of nonprogression) in 13 patients. CONCLUSIONS: TAK-285 was generally well tolerated at the RP2D. Distribution in human CSF was confirmed, but the free concentration of the drug was below that associated with biologically relevant target inhibition.

Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate renal impairment.

AIMS: To evaluate the pharmacokinetics and pharmacodynamics following a single dose of liposomal mifamurtide (L-MTP-PE, MEPACT(®)) in adult subjects with mild (calculated creatinine clearance [CLcr ] of 50-80 ml min(-1)) or moderate (CLcr 30-50 ml min(-1)) renal impairment in comparison with age-, weight- and gender-matched healthy subjects with normal renal function (CLcr >80 ml min(-1)). METHODS: Subjects received a 4 mg dose of liposomal mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for analysis of plasma pharmacokinetics of total and non-liposome-associated (free) mifamurtide and assessment of pharmacodynamics (changes in serum interleukin-6 [IL-6], tumour necrosis factor-α [TNF-α], C-reactive protein [CRP]). RESULTS: Thirty-three subjects were enrolled: nine with mild renal impairment, eight with moderate renal impairment and 16 healthy subjects. Geometric mean (%CV) AUCinf for total mifamurtide was 89.5 (58.1), 94.8 (27.8), 85.1 (29.0), 95.4 (18.1) nM h in the mild renal impairment, mild-matched healthy subject, moderate renal impairment and moderate-matched healthy subject groups, respectively. Mifamurtide clearance was not correlated with CLcr, estimated glomerular filtration rate or iohexol clearance (all r(2) < 0.01). AUCinf of free mifamurtide was similar across the renal function groups. There were no readily apparent differences in serum pharmacodynamic effect parameters (baseline-adjusted AUEClast for IL-6 and TNF-α and Emax for CRP) between the renal function groups. No subjects reported grade ≥3 or serious adverse events. CONCLUSIONS: Mild or moderate renal impairment does not alter the clinical pharmacokinetics or pharmacodynamics of mifamurtide. No dose modifications appear necessary for these patients based on clinical pharmacologic considerations.

Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate hepatic impairment.

AIMS: To evaluate the pharmacokinetics and pharmacodynamics after a single dose of liposomal mifamurtide (liposomal muramyl tripeptide phospatidyl ethanolamine; MEPACT(®)) in adult subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment in comparison with age-, weight- and sex-matched healthy subjects with normal hepatic function. METHODS: Subjects received a 4 mg dose of liposomal mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for pharmacokinetic and pharmacodynamic assessments (changes in serum interleukin-6, tumour necrosis factor-α and C-reactive protein). RESULTS: Thirty-seven subjects were enrolled: nine with mild hepatic impairment, eight with moderate hepatic impairment and 20 matched healthy subjects. Geometric least-square mean ratios of total mifamurtide AUCinf for the mild hepatic impairment and moderate hepatic impairment groups vs. matched healthy subjects were 105% (90% confidence interval, 83.6-132%) and 119% (90% confidence interval, 94.1-151%), respectively, which are below the protocol-specified threshold (150%) to require development of dose-modification recommendations. Pharmacodynamic parameters for changes in serum interleukin-6 and tumour necrosis factor-α concentrations were generally similar across hepatic function groups. Mifamurtide-induced increases in serum C-reactive protein were attenuated in the moderate hepatic impairment group, consistent with the liver being the major organ of C-reactive protein synthesis. No grade ≥3 adverse events were seen in subjects administered mifamurtide (4 mg). CONCLUSIONS: These results support the conclusion that mild or moderate hepatic impairment does not produce clinically meaningful effects on the clinical pharmacokinetics or pharmacodynamics of mifamurtide; no dose modifications are needed in these special patient populations based on clinical pharmacological considerations.

Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer.

Tremelimumab (CP-675,206) is a fully human monoclonal antibody specific for human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD152) in clinical development for patients with cancer. Blocking the CTLA-4 negative costimulatory receptor with the antagonistic antibody tremelimumab results in immune activation. Administration of tremelimumab to patients with locally advanced and metastatic melanoma has resulted in a subset of patients with durable objective tumor regressions. Its IgG(2) isotype minimizes the possibility of cytotoxic effects on activated T lymphocytes and cytokine release syndrome. Preclinical testing in vitro and in large animal models predicted the target concentrations of circulating antibody in humans necessary for a pharmacodynamic effect. Phase I clinical trials provided evidence of dose- or exposure-related effects consistent with the anticipated mechanism of action. Further clinical development has led to two ongoing registration trials in patients with metastatic melanoma: a phase III randomized trial of tremelimumab versus dacarbazine or temozolomide in previously untreated patients with advanced melanoma and a phase II trial of tremelimumab in previously treated patients with advanced melanoma.

Selective enhancement of cellular oxidative stress by chloroquine: implications for the treatment of glioblastoma multiforme.

Chloroquine is used in the treatment of malaria, a disease caused by infection with the parasite Plasmodium. Although chloroquine appears to possess diverse pharmacological activity, its plasmodicidal activity results from augmentation of parasite oxidative stress. Chloroquine also appears to augment oxidative stress in metabolically active mammalian cells, including human astroglial cells. The authors propose that chloroquine may augment oxidative stress induced by radiotherapy in the treatment of glioblastoma multiforme, enhancing therapeutic efficacy. Such an effect would be consistent with the known pharmacological effects of chloroquine observed in Plasmodium. Other selective redox agents, such as tempol and artemisinin, should be investigated clinically for therapeutic benefit when coadministered with combined radio- and chemotherapy for cancer.

A phase I and pharmacologic study of the matrix metalloproteinase inhibitor CP-471,358 in patients with advanced solid tumors.

BACKGROUND: Matrix metalloproteinases play a role in the process of tissue invasion and metastasis by degrading the extracellular matrix. Inhibitors of matrix metalloproteinases are therefore of interest as anticancer drugs. CP-471,358 is a matrix metalloproteinase inhibitor that in vitro demonstrates strong inhibition of matrix metalloproteinases 2 and 9. The drug can be administered orally without food restriction. STUDY DESIGN: An open-label phase I study was performed in patients with advanced solid tumors to assess the safety, tolerability, maximal tolerated dose (MTD) and pharmacokinetics of CP-471,358. The CP-471,358 doses studied were 50, 100 and 200 mg three times daily (TID) continuously, 50, 100 and 200 mg TID for 21 days followed by a 1-week treatment-free interval and 75 mg and 150 mg twice daily (BID) continuously. RESULTS: A total of 38 patients were treated in the study. The median number of cycles administered was two (range one to five). Myalgia and arthralgia were the most frequently observed adverse events (in 27 of 38 patients) and were observed at all dose levels and with all schedules except for the 150 mg BID continuous dosing level. In six patients National Cancer Institute (NCI) Common Toxicity Criteria (CTC) grade 3 myalgia/arthralgia was observed and this adverse event was considered to be the dose-limiting toxicity (DLT). Introduction of a 1-week treatment-free interval between cycles had no effect on the occurrence of myalgia/arthralgia. After cessation of treatment, arthralgia/myalgia was reversible in all patients. Other adverse events observed were fatigue and an increase of liver enzymes but these rarely exceeded CTC grade 2. Pharmacokinetic analysis showed that target efficacious concentrations were achieved throughout the morning dosing interval with 150 mg BID and 200 mg TID. CONCLUSION: The DLT of CP-471,358 was myalgia and arthralgia, an adverse event observed during treatment with most matrix metalloproteinase inhibitors. A drug-free interval of 1 week was unable to prevent the occurrence of these adverse effects. Clearly this represents a limitation for potential long-term use of this compound.

A phase I open label study of the farnesyltransferase inhibitor CP-609,754 in patients with advanced malignant tumors.

PURPOSE: The purpose of this phase I clinical trial was to determine the maximum-tolerated dose and toxicity of CP-609,754 in patients with solid tumors refractory to standard therapies, to determine the cellular effects of CP-609,754 on its molecular target (farnesyltransferase), and to determine the recommended phase II dose (RP2D) of this agent. EXPERIMENTAL DESIGN: Consenting patients with adequate bone marrow, liver, and renal function were enrolled with an accelerated dose strategy with single-patient parallel cohorts in whom the drug was given orally either once or twice daily. Once a dose-limiting toxicity was encountered or two patients developed Common Toxicity Criteria > or = grade 2 toxicities, a modified Fibonacci sequence was initiated. Blood samples were collected during cycle 1 for pharmacokinetic and pharmacodynamic analyses. RESULTS: A total of 68 cycles of CP-609,754 was administered to 21 patients enrolled in this study. The dose escalation was from 20 mg once daily to 640 mg twice per day, and at the highest dose level, one of six patients developed a dose-limiting toxicity of grade 3 neuropathy. The drug was otherwise well tolerated, and the maximum-tolerated dose was not reached because of the large number of tablets that would have been required for additional dose escalation. Pharmacokinetic analyses showed a proportional increase in exposure with dose, rapid oral absorption, and a half-life of approximately 3 hours. Pharmacodynamic results predict a 95% maximal inhibition of peripheral blood mononuclear cell farnesyltransferase activity 2 hours postdose, on average, with a dose of 400 mg twice per day of CP-609,754. CONCLUSIONS: On the basis of the safety findings and the pharmacokinetic and pharmacodynamic analyses, the RP2D of CP-609,754 is > or =640 mg twice per day.

A phase I and pharmacologic study of pyrazoloacridine and cisplatin in patients with advanced cancer.

Pyrazoloacridine (PZA, NSC366140, PD115934) is an acridine derivative currently undergoing clinical evaluation. In preclinical testing, PZA has shown selectivity for solid tumor cell lines, activity in hypoxic, noncycling, and multidrug-resistant cell lines, and synergy with cisplatin in a variety of lung cancer cell lines. In early phase I clinical studies PZA has shown modest activity in ovarian, cervical, and colon cancer. The purpose of the present study was threefold: to determine the maximally tolerated doses of the combination of PZA (3-h infusion) and cisplatin administered with and without Filgrastim (G-CSF) (Amgen, Thousand Oaks, CA) every 3 weeks in untreated or minimally pretreated patients, to describe and quantify the clinical toxicities of combination chemotherapy with PZA and cisplatin, and to evaluate the effects of drug sequencing on the toxicity profile and pharmacologic behavior of PZA. The starting doses in this dose-escalation trial were PZA 400 mg/m2 as a 3-h intravenous infusion and cisplatin 50 mg/m2 as a 1 mg/min intravenous infusion. The sequence of drugs was alternated with each successive course in each patient treated. Twenty-one patients with refractory solid tumors received 43 courses of therapy through four dose levels. Neutropenia was dose-limiting and defined the maximum tolerated dose of PZA 400 mg/m2 and cisplatin 50 mg/m2 without G-CSF support. With G-CSF support, nausea and vomiting were dose-limiting. The maximum tolerated and recommended doses for further study of this combination are PZA 600 mg/m2 over 3 h and cisplatin 50 mg/m2 followed by G-CSF support. Pharmacokinetic analysis showed that sequence does not impact on the pharmacokinetics of PZA when given in combination with cisplatin.

A lupus-like syndrome develops in mice lacking the Ro 60-kDa protein, a major lupus autoantigen.

Antibodies against a conserved RNA-binding protein, the Ro 60-kDa autoantigen, occur in 24-60% of all patients with systemic lupus erythematosus. Anti-Ro antibodies are correlated with photosensitivity and cutaneous lesions in these patients and with neonatal lupus, a syndrome in which mothers with anti-Ro antibodies give birth to children with complete congenital heart block and photosensitive skin lesions. In higher eukaryotes, the Ro protein binds small RNAs of unknown function known as Y RNAs. Because the Ro protein also binds misfolded 5S rRNA precursors, it is proposed to function in a quality-control pathway for ribosome biogenesis. Consistent with a role in the recognition or repair of intracellular damage, an orthologue of Ro in the radiation-resistant eubacterium Deinococcus radiodurans contributes to survival of this bacterium after UV irradiation. Here, we show that mice lacking the Ro protein develop an autoimmune syndrome characterized by anti-ribosome antibodies, anti-chromatin antibodies, and glomerulonephritis. Moreover, in one strain background, Ro-/- mice display increased sensitivity to irradiation with UV light. Thus, one function of this major human autoantigen may be to protect against autoantibody development, possibly by sequestering defective ribonucleoproteins from immune surveillance. Furthermore, the finding that mice lacking the Ro protein are photosensitive suggests that loss of Ro function could contribute to the photosensitivity associated with anti-Ro antibodies in humans.