A systematic approach to workplace-based assessment for international medical graduates.

OBJECTIVES: To test whether a summative workplace-based assessment (WBA) is feasible and acceptable for international medical graduates (IMGs). DESIGN, SETTING AND PARTICIPANTS: A 6-month trial with 27 IMGs from teaching hospitals in Newcastle, Australia. IMGs were assessed by 65 trained assessors from different disciplines, using blueprinted, preset criteria. MAIN OUTCOME MEASURES: Mini-clinical evaluation exercises, case-based discussions, in-training assessments and multisource feedback. At the end of the trial, assessors and candidates gave feedback. RESULTS: All IMGs were successful at the end of the assessment. The format was well received and acceptable to the candidates and assessors. CONCLUSIONS: WBA is feasible and acceptable to assessors and candidates for assessment of IMGs, but it is intensive in use of resources and time.

Absence of food effect on the pharmacokinetics of telbivudine following oral administration in healthy subjects.

The influence of food on the pharmacokinetics of telbivudine, a candidate antiviral agent against hepatitis B virus (HBV), was investigated in healthy adult subjects following a 600-mg oral dose administered with and without a high-fat/high-calorie meal. Telbivudine was well tolerated under fasting and fed conditions. Oral absorption of telbivudine as measured by maximum plasma concentration (Cmax), time to reach Cmax (Tmax), and area under the plasma concentration-time curve (AUC(0-t) and AUC(0-infinity)) was not altered by food intake immediately before oral dosing. Values of Cmax, Tmax, and AUC were comparable when telbivudine was administered under fed and fasting conditions. Results from this study indicated that the absorption of telbivudine was not affected by a high-fat/high-calorie meal; telbivudine can therefore be administered orally with no regard to the timing of meals.

Pharmacokinetics of telbivudine in healthy subjects and absence of drug interaction with lamivudine or adefovir dipivoxil.

Two phase I studies were conducted to assess the plasma pharmacokinetics of telbivudine and potential drug-drug interactions between telbivudine (200 or 600 mg/day) and lamivudine (100 mg/day) or adefovir dipivoxil (10 mg/day) in healthy subjects. Study drugs were administered orally. The pharmacokinetics of telbivudine were characterized by rapid absorption with biphasic disposition. The maximum concentrations in plasma (Cmax) were reached at median times ranging from 2.5 to 3.0 h after dosing. Mean single-dose Cmax and area under the plasma concentration-time curve from time zero to infinity (AUC0-infinity) were 1.1 and 2.9 microg/ml and 7.4 and 21.8 microg . h/ml for the 200- and 600-mg telbivudine doses, respectively. Steady state was reached after daily dosing for 5 to 7 days. The mean steady-state Cmax and area under the plasma concentration-time curve over the dosing interval (AUCtau) were 1.2 and 3.4 microg/ml and 8.9 and 27.5 microg . h/ml for the 200- and 600-mg telbivudine repeat doses, respectively. The steady-state AUCtau of telbivudine was 23 to 57% higher than the single-dose values. Concomitant lamivudine or adefovir dipivoxil did not appear to significantly alter the steady-state plasma pharmacokinetics of telbivudine; the geometric mean ratios and associated 90% confidence interval (CI) for the AUCtau of telbivudine alone versus in combination were 106.3% (92.0 to 122.8%) and 98.6% (86.4 to 112.5%) when coadministered with lamivudine and adefovir dipivoxil, respectively. Similarly, the steady-state plasma pharmacokinetics of lamivudine or adefovir were not markedly affected by the coadministration of telbivudine; the geometric mean ratios and associated 90% CI, alone versus in combination with telbivudine, were 99.0% (87.1 to 112.4%) and 92.2% (84.0 to 101.1%), respectively, for the lamivudine and adefovir AUCtau values. Moreover, the combination regimens studied were well tolerated in all subjects. The results from these studies provide pharmacologic support for combination therapy or therapy switching involving telbivudine, lamivudine, and adefovir dipivoxil for the treatment of chronic hepatitis B virus infection.

Pharmacokinetics of telbivudine following oral administration of escalating single and multiple doses in patients with chronic hepatitis B virus infection: pharmacodynamic implications.

The pharmacokinetics of telbivudine were evaluated in adult patients with chronic hepatitis B virus (HBV) infection following once-daily oral administration at escalating doses of 25, 50, 100, 200, 400, and 800 mg/day for 4 weeks. Telbivudine was rapidly absorbed after oral administration, with the median times T(max) to the maximum plasma concentration (C(max)) ranging from 0.8 to 3.0 h postdosing across cohorts. Single-dose and steady-state maximum C(max)s and the areas under the plasma concentration-time curve from time zero to time t (AUC(0-t)s) increased proportionally with dose. At steady-state, the values of C(max) and AUC(0-t) were higher than those obtained after the administration of a single dose, indicative of a slight accumulation, with the ratios of the steady-state value to the value after the administration of a single dose ranging from 1.14 to 1.49 for C(max) and from 1.40 to 1.70 for AUC(0-t). While the elimination of telbivudine from plasma was apparently monophasic over the 8-h sampling period, the substantial steady-state trough plasma levels observed in the groups receiving doses of 100 to 800 mg were clearly indicative of the presence of a second slower elimination phase, with the mean estimated half-lives ranging from 29.5 to 41.3 h by compartmental modeling analysis. Pharmacokinetic and pharmacodynamic analyses by using maximum-effect modeling established a quantitative relationship between a reduction in serum HBV DNA levels and parameters of drug exposure, in particular, the steady-state C(max) and AUC(0-t). In summary, this study showed that telbivudine exhibits dose-proportional plasma pharmacokinetics with sustained steady-state drug exposure and exposure-related antiviral activity, supporting the need for further clinical studies by use of a once-daily regimen in patients with chronic HBV infection.

A dose-finding study of once-daily oral telbivudine in HBeAg-positive patients with chronic hepatitis B virus infection.

Current therapy for chronic hepatitis B is suboptimal as a result of limited durable response rates, cumulative viral resistance, and/or poor tolerability. Telbivudine has potent antiviral activity against hepatitis B virus (HBV) in vitro and in the woodchuck model and has a promising preclinical safety profile. In this first clinical study of telbivudine, safety, antiviral activity, and pharmacokinetics were assessed in 43 adults with hepatitis B e antigen-positive chronic hepatitis B. This placebo-controlled dose-escalation trial investigated 6 telbivudine daily dosing levels (25, 50, 100, 200, 400, and 800 mg/d); treatment was given for 4 weeks, with 12 weeks' follow-up. Serum HBV DNA levels were monitored via quantitative polymerase chain reaction. The results indicate that telbivudine was well tolerated at all dosing levels, with no dose-related or treatment-related clinical or laboratory adverse events. telbivudine plasma pharmacokinetics were dose-proportional within the studied dose range. Marked dose-related antiviral activity was evident, with a maximum at telbivudine doses of 400 mg/d or more. In the 800 mg/d cohort, the mean HBV DNA reduction was 3.75 log10 copies/mL at week 4, comprising a 99.98% reduction in serum viral load. Correspondingly, posttreatment return of viral load was slowest in the high-dose groups. Viral dynamic analyses suggested a high degree of efficiency of inhibition of HBV replication by telbivudine and helped refine selection of the optimal dose. In conclusion, these results support expanded clinical studies of this new agent for the treatment of hepatitis B.