Pharmacokinetic-pharmacodynamic (PK-PD) modeling for a new antihypertensive agent (neutral metalloendopeptidase inhibitor SCH 42354) in patients with mild to moderate hypertension

SCH 42354, a neutral metalloendopeptidase (NEP) inhibitor, is the pharmacologically active form of the prodrug SCH 42495. It exerts antihypertensive effects by potentiating atrial natriuretic peptide (ANP) activity through inhibition of its hydrolysis by NEP. The objective of this study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SCH 42354 in hypertensive males. SCH 42495 12.5 to 400 mg was administered orally to hypertensive men twice daily in a double-blind, placebo controlled multiple-dose parallel group design. Plasma SCH 42354 concentration and diastolic blood pressure (DBP) data were used to develop a PK-PD model using two approaches. In the first (non-integrated) approach, the link model was used to predict effect-site concentrations, and was applied to data obtained at the 300 and 400 mg BID doses only; data at the other (lower) doses were not amenable to modeling because of high variability. Effect-site concentration and DBP data were then fit to a sigmoid E_max PD model. For the 300 mg BID dose, PD parameters were: maximum effect (E_max), 8.1mmHg; no-drug effect (Eo), 3.6 mmHg; concentration corresponding to 50% of maximum response (EC₅₀), 0.87 g·ml^–1; and gamma, 3.9. In the second (time-integrated) approach, plasma SCH 42354 concentration and effect data obtained over the entire dose range were integrated with respect to time. Average plasma concentration and DBP data were then fit to a simple E_max PD model. PD parameters obtained over the dose range were: E_max, 10.3 mmHg; Eo, 2.0 mmHg; and EC₅₀, 0.7 g·ml^–1. These were similar to the estimates obtained from the first approach, demonstrating that the integrated (average) data allow PK-PD modeling over the (entire) dose range. The analysis showed that, at steady-state, a 400 mg BID dose of SCH 42495 produced an approximate 10 mmHg decrease in DBP in hypertensive males; the average plasma SCH 42354 concentration attained at this dose was approximately 1.8 g·ml^–1.     

Characterization of AUCs from Sparsely Sampled Populations in Toxicology Studies

Purpose. The objective of this work was to develop and validate blood sampling schemes for accurate AUC determination from a few samples (sparse sampling). This will enable AUC determination directly in toxicology studies, without the need to utilize a large number of animals. Methods. Sparse sampling schemes were developed using plasma concentration-time (Cp-t) data in rats from toxicokinetic (TK) studies with the antiepileptic felbamate (F) and the antihistamine loratadine (L); Cp-t data at 13–16 time-points (N = 4 or 5 rats/time-point) were available for F, L and its active circulating metabolite descarboethoxyloratadine (DCL). AUCs were determined using the full profile and from 5 investigator designated time-points termed critical time-points. Using the bootstrap (re-sampling) technique, 1000 AUCs were computed by sampling (N = 2 rats/point, with replacement) from the 4 or 5 rats at each critical point. The data were subsequently modeled using PCNONLIN, and the parameters (k_a, k_e, and V_d) were perturbed by different degrees to simulate pharmacokinetic (PK) changes that may occur during a toxicology study due to enzyme induction/inhibition, etc. Finally, Monte Carlo simulations were performed with random noise (10 to 40%) applied to Cp-t and/or PK parameters to examine its impact on AUCs from sparse sampling. Results. The 5 time-points with 2 rats/point accurately and precisely estimated the AUC for F, L and DCL; the deviation from the full profile was ~10%, with a precision (%CV) of ~15%. Further, altered kinetics and random noise had minimal impact on AUCs from sparse sampling. Conclusions. Sparse sampling can accurately estimate AUCs and can be implemented in rodent toxicology studies to significantly reduce the number of animals for TK evaluations. The same principle is applicable to sparse sampling designs in other species used in safety assessments.     

Safety,tolerability, pharmacokinetics,and pharmacodynamics of a TLR7 agonist prodrug RO6870868 in healthy volunteers

RO6870868 is an oral prodrug of the toll‐like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a first‐in‐human, phase I, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200–2000 mg). Single oral doses were generally well‐tolerated with a predictable safety profile associated with dose‐dependent increases in systemic interferon. No serious adverse events (AEs) were reported and no subject withdrew from the study due to an AE. No clinically significant changes were observed in vital signs, electrocardiograms, or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half‐life ranging 2–6 h across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC_0‐∞) increasing proportionally with dose. A pattern of dose and time‐dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose‐dependent manner with adequate safety and tolerability. Single‐dose data in healthy volunteers are useful to evaluate safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Toll‐like receptor 7 (TLR7) agonists induce broad immune‐enhancing effects and may play a role in overcoming the adaptive and innate immune defects in chronic hepatitis B infection.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of RO6870868 (a prodrug of the specific TLR7 agonist RO6871765) in healthy volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

RO6870868 was safe and acceptably tolerated across the dose range in healthy volunteers. Oral administration results in the rapid appearance of the active TLR7 agonist RO6871765 and leads to a profile of gene expression typical for TLR7 agonism, including activation of interferon and interferon‐response genes. Gene activation occurs at RO6871765 exposure associated with single RO6870868 doses greater than or equal to 800 mg, with a plateau for several markers at doses between 1200 mg and 1600 mg.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The study results help to guide dose and regimen selection for clinical trials with RO6870868 and other potent TLR7 activators.     

Down-regulation of the pharmacokinetic-pharmacodynamic response to interleukin-12 during long-term administration to patients with renal cell carcinoma and evaluation of the mechanism of this "adaptive response" in mice.

BACKGROUND: Interleukin-12 (IL-12) is a cytokine that promotes type-1 helper T-cell responses and may have therapeutic utility in the treatment of cancer, asthma, and a variety of infectious diseases. METHODS: In a phase I trial, recombinant human IL-12 (rHuIL-12) was administered subcutaneously once a week at a fixed dose of 0.1 to 1.0 microg/kg to 24 patients with renal cell carcinoma. A similar study was later performed in mice to evaluate the mechanism of down-regulation of pharmacokinetic-pharmacodynamic response observed in patients with cancer. RESULTS: Adverse events, serum IL-12 levels, and serum levels of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) produced in response to IL- 12 were all maximum in the week after the first dose of rHuIL-12 and decreased after long-term administration. Similar to these results, repetitive subcutaneous administration of recombinant mouse IL-12 (rMoIL-12) to normal mice led to down-regulation of serum levels of IL-12 and IFN-gamma measured 5 hours after rMoIL-12 injection. Down-regulation of IL-12 serum levels was inversely correlated with the up-regulation of IL-12 receptor expression and may be the result of increased clearance of rMoIL-12 from serum by binding to lymphoid cells expressing increased amounts of IL-12 receptor. The down-regulation of serum IFN-gamma levels correlated with decreased IFN-gamma messenger ribonucleic acid expression and may result from feedback inhibition of IL-12 signaling or from a more specific inhibition of IFN-gamma synthesis. CONCLUSION: Administration of rHuIL-12 in fixed weekly doses resulted in decreased serum levels of IL-12 and of IFN-gamma, a secondary cytokine believed to be critical to response of IL-12. A better understanding of the complex regulation of the pharmacokinetic-pharmacodynamic response to IL-12 should facilitate the development of more effective dosing regimens for its use in the clinic.     

The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP™) predicts in vivo metabolic inhibition

Background Erlotinib is an orally active antitumor agent. Analyses in vitro using human liver microsomes and recombinant enzymes showed that erlotinib was metabolized primarily by CYP3A4, with a secondary contribution from CYP1A2. Methods A computer-based simulation model, SimCYP™, predicted that CYP3A4 contributed to ∼70% of the metabolic elimination of erlotinib, with CYP1A2 being responsible for the other ∼30%. A drug-drug interaction study was therefore conducted for erlotinib and a potent CYP3A4 inhibitor, ketoconazole, in healthy male volunteers to evaluate the impact of CYP3A4 inhibition on erlotinib exposure. Results Ketoconazole caused an almost two-fold increase in erlotinib plasma area under the concentration curve and in maximum plasma concentration. This is consistent with the SimCYP™ prediction of a two-fold increase in erlotinib AUC, further validating a primary (∼70%) role of CYP3A4 in erlotinib elimination. Conclusion Prediction of clinically important drug-drug interaction with SimCYP™ using in vitro human metabolism data can be a powerful tool during early clinical development to ensure safe administration of anticancer drugs, which are often co-administered at maximum tolerated doses with other drugs as part of a palliative treatment regimen.     

The effect of rifampicin,a prototypical CYP3A4 inducer,on erlotinib pharmacokinetics in healthy subjects

Purpose

Erlotinib, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine is approved for the treatment for non-small cell lung cancer and pancreatic cancer. Because erlotinib is metabolized predominately by CYP3A4, co-administration of compounds that increase CYP3A4 activity may alter the efficacy and safety of erlotinib therapy. Two phase I studies were conducted in healthy male subjects to evaluate the effect of pre- or co-administered rifampicin, a CYP3A4 inducer, on the pharmacokinetics of erlotinib.

Methods

Study 1 included Groups A (erlotinib 150 mg days 1 and 15, rifampicin 600 mg days 8–14) and B (erlotinib 150 mg days 1 and 15) in a parallel group study design. Study 2 subjects received erlotinib 150 mg day 1, erlotinib 450 mg day 15, and rifampicin 600 mg days 8–18. The primary endpoint in each study was the ratio of exposure (AUC_0–∞ and C _max) between days 1 and 15. Urinary cortisol metabolic induction ratios were determined in Study 1 for Group A subjects only.

Results

In Study 1, the geometric mean ratios of AUC_0–∞ and C _max were 33 and 71 %, respectively, and the mean cortisol metabolic index increased from 7.4 to 27.0, suggesting cytochrome P450 (CYP) enzyme induction. In Study 2, the geometric mean ratios for AUC_0–∞ and C _max were 19 and 34 % (when dose adjusted from 450 to 150 mg erlotinib), respectively, a greater relative decrease than observed in Study 1.

Conclusions

Erlotinib exposure (AUC_0–∞ and C _max) was reduced after pre- or concomitant dosing with rifampicin. Doses of ≥450 mg erlotinib may be necessary to compensate for concomitant medications with strong CYP3A4 enzyme induction effect.     

Pharmacokinetic interaction study of ritonavir-boosted saquinavir in combination with rifabutin in healthy subjects

The effect of multiple doses of rifabutin (150 mg) on the pharmacokinetics of saquinavir-ritonavir (1,000 mg of saquinavir and 100 mg of ritonavir [1,000/100 mg]) twice daily (BID) was assessed in 25 healthy subjects. Rifabutin reduced the area under the plasma drug concentration-time curve from 0 to 12 h postdose (AUC(0-12)), maximum observed concentration of drug in plasma (C(max)), and minimum observed concentration of drug in plasma at the end of the dosing interval (C(min)) for saquinavir by 13%, 15%, and 9%, respectively, for subjects receiving rifabutin (150 mg) every 3 days with saquinavir-ritonavir BID. No effects of rifabutin on ritonavir AUC(0-12), C(max), and C(min) were observed. No adjustment of the saquinavir-ritonavir dose (1,000/100 mg) BID is required when the drugs are administered in combination with rifabutin. The effect of multiple doses of saquinavir-ritonavir on rifabutin pharmacokinetics was evaluated in two groups of healthy subjects. In group 1 (n = 14), rifabutin (150 mg) was coadministered every 3 days with saquinavir-ritonavir BID. The AUC(0-72) and C(max) of the active moiety (rifabutin plus 25-O-desacetyl-rifabutin) increased by 134% and 130%, respectively, compared with administration of rifabutin (150 mg) once daily alone. Rifabutin exposure increased by 53% for AUC(0-72) and by 86% for C(max). In group 3 (n = 13), rifabutin was coadministered every 4 days with saquinavir-ritonavir BID. The AUC(0-96) and C(max) of the active moiety increased by 60% and 111%, respectively, compared to administration of 150 mg of rifabutin once daily alone. The AUC(0-96) of rifabutin was not affected, and C(max) increased by 68%. Monitoring of neutropenia and liver enzyme levels is recommended for patients receiving rifabutin with saquinavir-ritonavir BID.     

Erlotinib in combination with capecitabine and docetaxel in patients with metastatic breast cancer: a dose-escalation study

Capecitabine added to docetaxel extends survival in metastatic breast cancer (MBC) and shows additive efficacy with erlotinib in pre-clinical studies. This study aimed to determine the maximum-tolerated dose (MTD) of capecitabine/docetaxel with erlotinib and assess tolerability, anti-tumour activity and potential pharmacokinetic interactions. Three treatment cohorts were assessed, using different dosing regimens. A total of 24 women with MBC were enrolled sequentially. The regimen comprising erlotinib 100mg/day continuously, capecitabine 825mg/m2 bid on days 1 to 14 and docetaxel 75mg/m2 intravenously every 3 weeks on day 1 was well tolerated and was established as the MTD. Overall response rate was 67%, comprising two complete and 12 partial responders in 21 assessable patients. The most common treatment-related adverse events were gastrointestinal disorders and skin toxicities. Pharmacokinetic studies showed that exposure to the three drugs was not reduced when given in combination. These encouraging preliminary results warrant further trials of the combination in MBC.     

A phase Ib dose-escalation study of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer patients.

BACKGROUND: Dysregulation of the epidermal growth factor receptor (HER1/EGFR) has been reported in colorectal cancer (CRC). Erlotinib is a potent inhibitor of HER1/EGFR-mediated signaling. This trial of patients with metastatic CRC (MCRC) examined the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin (XELOX), a regimen with established efficacy. PATIENTS AND METHODS: Patients previously untreated or treated with one line of 5-fluorouracil and/or irinotecan received escalating oral doses of erlotinib (daily), capecitabine (days 1-14) and i.v. oxaliplatin (day 1 of a 21-day cycle). RESULTS: The first six patients in cohort 1 (erlotinib 100 mg/day, capecitabine 825 mg/m(2) twice daily, oxaliplatin 130 mg/m(2)) had no dose-limiting toxicities (DLTs). In cohort 2 (capecitabine increased to 1000 mg/m(2) twice daily), two of six patients had DLTs. When cohort 2 was expanded to 11 patients two further DLTs occurred, exceeding the definition of MTD. Cohort 1 was expanded to 12 patients, and no DLTs occurred. The most common adverse events (AEs) were diarrhea and rash. There was a trend for reduced capecitabine concentrations in the presence of erlotinib. While this was not statistically significant, the possibility of an interaction affecting capecitabine PK cannot be excluded. Antitumor activity was observed in both cohorts (one complete and four partial responses, and stable disease in 11 patients). CONCLUSION: The MTD for this combination in MCRC is capecitabine 825 mg/m(2) twice daily days 1-14, oxaliplatin 130 mg/m(2) day 1 and erlotinib 100 mg/day of a 21-day cycle. The combination was well tolerated at the MTD, with no unexpected AEs. The use of this combination in MCRC warrants further investigation.