| Objective: 1.To assess the safety and tolerance of adefovir in Chinese healthy volunteers afer single (5, 10, 20, 40 and 60mg) and multiple (10mg) oral doses of adefovir dipivoxil tablets, to confirm and validate the clinical conventional oral dosage regimen. 2. To study the pharmacokinetics (absorption, distribution and elimination) of adefovir in healthy volunteers after single (10, 20, and 40mg)and multiple (lOmg) doses of adefovir dipivoxil tablets, and compare the changes of pharmacokinetic parameters at different doses and accumulating behavior of multiple doses. 3. To study the pharmacokinetics (absorption, distribution and elimination) of adefovir in healthy volunteers in fasting and dining conditions, and to evaluate the effect of food on pharmacokinetic parameters and provide evidence for phase II clinical trials.Methods: 1. 42 healthy volunteers with half female and half male were enrolled in the tolerance study of single oral administration of adefovir dipivoxil. All subjects were randomly divided into 5,10,20,40 and 60mg dose-groups (6-10 subjects in each group) balanced by sex and weight. Clinical symptoms, vital signs, electrocardiogram, routine blood test, routine urine test, prothrombin time and blood biochemical test of all volunteers were recorded and evaluated before and after single oral administration of adefovir dipivoxil tablets. 2. 10 healthy volunteerswith half female and half male were enrolled in the tolerance study of multiple oral administration of adefovir dipivoxil. The clinical symptoms, vital signs, electrocardiogram, routine blood test, routine urine test, prothrombin time and blood biochemical test of all volunteers before and after multiple oral administration of adefovir dipivoxil tablets (lOmg, qd, for 7days) were recorded and evaluated. 3. 9 healthy male volunteers were divided into 3 groups according to 3X3 Latin square design and orally given 10, 20 and 40mg adefovir dipivoxil tablets for single dose pharmacokinetics study. The serum and urine samples were collected in schedul and analyzed by LC-MS/MS, the pharmacokinetic parameters of adefovir were calculated by DAS software, and the adverse reaction, if any, was recorded at same time. 4. 10 healthy male volunteers were divided into 2 groups according to two cross-over design and orally given lOmg adefovir dipivoxil tablets to investigate the effect of food on the pharmacokinetic parameters of adefovir. The serum samples were collected in schedule and analyzed by LC-MS/MS, the pharmacokinetic parameters of adefovir were calculated by DAS software, and the adverse reaction, if any, was recorded at same time. 5. 10 healthy volunteers with half female and half male were enrolled in the pharmacokinetics study of multiple oral administration of lOmg adefovir dipivoxil tablets once daily for 7 days. The serum samples were collected in schedul and analyzed by LC-MS/MS, the pharmacokinetic parameters of adefovir were calculated by DAS software, the pharmacokinetic characteristics were evaluated and the adverse reaction, if any, was recorded at same time.Result: 1. No serious adverse reactons and significant clinical changes in clinical symptoms, vital signs and laboratory tests after single oral administration were found in all dose-groups, except the slight elevations of ALT, TBIL, DBLL and IBIL and occurrence of some gastrointestinal symptoms such as nausea and diarrhea. 2. No seriousadverse reactons and significant clinical changes were found after multiple oral administration (lOmg, qd, for 7days), except the slight elevation of ALT, CK and LDH and accurance of some clinical symptoms such as asthenia, nausea and diarrhea. 3. Adefovir dipivoxil was rapidly hydrolyzed into adefovir in human body. The main pharmacokinetic parameters of adefovir after single oral administration of 10, 20 and 40mg adefovir dipivoxil tablets were as follows: t1/2 6.81+0.84, 7.45±1.13 and 7.68±1.75h, Tmax 1.28±0.36, 1.14±0.6 and 1.11±0.4h, Cmax 23.53±4.87, 47.94±8.34 and 85. 31 ± 18. 79 μg ·L-1, AUC0-24 229. 41±37.00, 433.62±111. 33 and 706.66±185. 85 μg·L-1·h, AUO0-∞ 233.07 ± 37.16, 437. 85±111.13 and 712. 21 ±185. 31μg ·L-1·h, excretion rate from urine 34.03 ± 4.37%, 36.56 ± 10.28% and 35.40±13.68%, respectively. An excellent linear correlation was obtained between Cmax (r=0.9976), AUC (r=0.9943) and doses. 4. The pharmacokinetic parameters such as t1/2, Cmax and AUC of adefovir were not affected by food in a two cross-over design study , but Tmax was prolonged after dining compared to fasting condition. The main pharmacokinetic parameters of adefovir after single oral administration of lOmg adefovir dipivoxil tablets in fasting and dining conditions were as follows: t1/2 7.43 ± 0.92 and 6. 97 ± 0. 65h, Tmax 1.11 ±0.31 and 2. 61±0.42h, Cmax 24. 67±4. 03 and 23. 26±5. 31 μg · L-1, AUC0-24 220. 68±39. 09 and 201. 78±38. 41 μg ·L-1 · h, AUC0-∞225. 04±39. 04 and 205. 71± 38. 75 μg · L-1 · h, respectively. 5. The main pharmacokinetic parameters of adefovir orally given lOmg adefovir dipivoxil tablets once daily for 7days were as follows: t1/2 6. 37±0. 85h, Tmax 1.47±0. 48h, Cmax 23. 67±5. 23μg·L-1, AUC0-24 218. 92±41. 78μg · L-1 ·h and AUC0-∞ 222. 14±42. 03 μg · L-1· h, Css was achieved after 4 days and no accumulation was observed. Conclusion: 1. Adefovir dipivoxil was sai'e and no serious adverse reactions were found after single oral dose of 5mg, 10mg, 20mg, 40mg and 60mg of adefovir dipivoxil tablets. Some adverse reactions such asasthenia, nausea and diarrhea and abnormal laboratory test items, such as slight elevation of ALT, TBIL, DBIL and IBIL were found, which were tolerable and recovered to normal by themselves. 2. No significant clinical changes were found in clinical symptoms, vital signs and laboratory tests after multiple oral dose of 10mg adefovir dipivoxil tablets once daily for 7days, except that slight elevation of ALT, CK and LDH and some symptoms such as asthenia, nausea and diarrhea were observed in several subjects. 3. An excellent linear correlation was obtained between Cmax, AUC and dose respectively after single oral dose of 10, 20 and 40mg adefovir dipivoxil. 4. The t1/2 Cmax and AUC of adefovir were not affected by food, but Tmax was prolonged from 1. 11±0.31h to 2.61 ±0.42h. 5. No accumulation was found after multiple oral dose of lOmg adefovir dipivoxil. 6. The trial was in success and all volunteers were in good compliance. Some adverse reactions were observed after single and multiple oral administration of adefovir dipivoxil in schedule doses, but slight and tolerable, and did not affect the process of the trial. No volunteers dropped out during the whole trial for any reasons.
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