Doripenem II Doripenem II doripenem DRPM II DRPM DRPM mg mg mg mg 9. 9 9. 9. 8. 9 9. 9.9 GPT. GOT.8. 9 98. 9.9 9 9.9 9. II DRPM Key words: carbapenem doripenem respiratory tract infection urinary tract infection early phase II clinical study Doripenem DRPM Stenotrophomonas maltophilia β β I DHP-I imipenem meropenem
Table. Clinical sites and investigators Sites Sapporo Hospital of Hokkaido Railway Company Sendai Kosei Hospital Fukushima Prefectural Aizu General Hospital Doai Memorial Hospital The Jikei University School of Medicine National Hospital Organization Utsunomiya National Hospital Toranomon Hospital School of Medicine, Kyorin University Kugayama Hospital National Hospital Organization Tokyo National Hospital Kanagawa Prefecture Midwives and Nurses Training School Hospital Kanagawa Prefectural Cardiovascular and Respiratory Disease Center Institute of Medical Science, St. Marianna University School of Medicine Niigata University, School of Medicine Shinrakuen Hospital Department of Medicine, Kawasaki Medical School Kawasaki Medical School, Kawasaki Hospital School of Medicine, Kurume University Nagasaki University School of Medicine Institute of Tropical Medicine, Nagasaki University Oita University Faculty of Medicine Faculty of Medicine, University of the Ryukyus Sapporo Medical University School of Medicine The Jikei University School of Medicine Faculty of Medicine, The University of Tokyo Tokyo Kyosai Hospital Tokai University, School of Medicine Tokai University Oiso Hospital Fujita Health University School of Medicine Hiratsuka City Hospital Gifu University School of Medicine Kobe University, School of Medicine Kawachi General Hospital Hyogo Prefectural Rehabilitation Center Okayama University Medical School Tottori City Hospital Jyuzen General Hospital Faculty of Medicine, Kyushu University Faculty of Medicine, Kagoshima University Wakayama Medical University, School of Medicine Kyoto Prefectural University of Medicine Department Respiratory Disease Allergy and Respiratory Disease Respiratory Disease Respiratory Disease Respiratory Disease Respiratory Diseases Surgery Obstetrics and Gynecology Investigators Yohmei Hiraga, Mitsuhide Ohmichi Yushi Nakai, Yoshihiro Honda, Satoshi Shoji, Hiroshi Takahashi Kazunao Niizuma Yasuyuki Sano, Chuhei Ogawa Osamu Sakai, Kohya Shiba Kazuhisa Okada, Yasushi Nakazawa Koichiro Nakata Hiroyuki Kobayashi Hiroshi Sugiura Harumi Shishido, Sachiko Tanoue, Kana Miyata Fumio Matsumoto Shigeki Odagiri, Kaneo Suzuki, Satoshi Inoue, Yuji Watanuki, Yoshihiro Hirai, Ishimaru Yuriko, Kenichi Takahashi Jingoro Shimada, Kazuo Ishida Masaaki Arakawa Nobuki Aoki Toshiharu Matsushima, Yoshihito Niki, Naoyuki Miyashita Niro Okimoto, Makoto Kimura Kotaro Oizumi, Nobuyuki Suzuki, Toru Rikimaru, Takashi Yoshizumi, Yasuko Kim, Tomomi Shimizu, Yoshiko Sueyasu, Seiji Ueda Shigeru Kohno, Hironobu Koga, Hiroaki Hazama, Kazunori Tomono, Kazuo Ohba Tsuyoshi Nagatake, Hideaki Amano, Misao Tao Masaru Nasu Atsushi Saito, Futoshi Higa, Masao Tateyama Taiji Tsukamoto, Takasi Sato Yukihiko Ohishi Kazuki Kawabe, Yasushi Saiko Isao Saito, Masahiko Yoshida Nobuo Kawamura, Yasuhisa Harashima Keishi Okada, Aiichiro Masuda Yorio Naide, Kiyotaka Hoshinaga, Masaki Horiba Keizo Suzuki Yukimichi Kawada, Shigehiko Ozeki Sadao Kamidono, Toshio Imai Shusou Den Atsushi Sengoku, Maki Kobayashi Hiroyuki Ohmori, Kouichi Monden Shunji Hayata Satoshi Uno Joichi Kumazawa, Yoshihumi Abe Yoshitada Ohi, Kazuya Kawahara Hiroshi Tanimura, Koichi Murakami, Hiroaki Nakai, Manabu Kawai, Shinji Yamazoe Hideo Honjo, Jinsuke Yasuda
Doripenem II Table. Exclusion criteria Subjects should not meet any of the following exclusion criteria:. Subjects who are suspected to indicate a bad prognosis due to severe symptoms. Subjects with severe cardiac disturbance, hepatic dysfunction, or renal dysfunction. Subjects where the assessment of efficacy and safety of antibiotics is difficult due to severe or progressive underlying diseases and/or complications. Subjects with a history of epilepsy or with central nervous system disorders. Subjects whose intracutaneous reaction to DRPM is Positive or Impossible to determine whether it is positive or negative. Subjects with a history of hypersensitivity to beta-lactam antibiotics carbapenems, cephems, penicillins, etc.. Subjects who are pregnant women, lactating women, or women suspected of being pregnant 8. Subjects where, prior to administration of DRPM, causative organisms are obviously resistant to DRPM S. maltophilia, Mycoplasma, fungi, etc. 9. Subjects who need diuretics bumetanide, furosemide, etc.. Subjects who have taken other investigational drugs just prior to administration of DRPM. Subjects who are getting better due to the treatment with other antibiotics prior to administration of DRPM. Aged subjects who have or may have disorders that might affect the assessment of efficacy of DRPM. Subjects who, in the opinion of the investigator, are otherwise unsuited for participation in this study I, mg, mg 8.9... µ g ml mg DRPM 8 GCP I 99 99 Table UTI Table DRPM mg DRPM mg DRPM µ g ml I mg mg mg I mg I erythromycin beclometasone dipropionate
CRP X UTI dip slide CFU ml PaO PaCO ph GOT GPT ALP γ -glutamyl transpeptidase γ -GTP lactate dehydrogenase LDH leucine aminopeptidase LAP BUN Cr Ccr β Na K Cl CRP CF IHA mg 8 Bioassay UTI
Doripenem II II Table Table 9. Table mg 9. mg mg 9 mg 9 Table UTI UTI UTI UTI 9.8 Table 9 9 Pseudomonas aeruginosa Table 8 8. 9 9. Table 9 9 9 Table P. aeruginosa 9. 9 9.9 8 9. Enterococcus faecalis P. aeruginosa Table Haemophilus influenzae P. aeruginosa Escherichia coli Staphylococcus spp. Klebsiella pneumoniae P. aeruginosa 8. 9 Table.8
Table. Patients profiles Demographics Gender Age yr Dose Treatment days History of allergy Previous antibacterial drug Category number of patients Male Female -9-9 -9-9 -9 - Complicated cystitis Complicated pyelonephritis Others mg /day mg /day mg /day mg /day - - -8 9- - - Yes No Yes No patients 8 8 Table. Patients assessed for efficacy and safety of DRPM patients Efficacy Number of patients Safety Safety Symptom Laboratory data Safety rate Usefulness Respiratory infection Chronic respiratory tract infection Secondary infection of chronic respiratory disease Other respiratory infection Urinary tract infection Complicated urinary tract infection Cystitis Pyelonephritis 9 9 9 9 Other urinary tract infection number of patients Number of exceptional patients
Doripenem II Table. Correlation between diagnosis and clinical response patients Excellent Clinical evaluation Good Fair Poor Efficacy Chronic respiratory tract infection 9.. 8 9. Secondary infection of chronic respiratory disease 9. Complicated urinary tract infection Cystitis Pyelonephritis 9 9.. 9.8 8 9. Efficacy: Excellent Good / patients Table. Correlation between daily dose and clinical response mg Chronic respiratory tract infection / / Secondary infection of chronic respiratory disease / / Complicated urinary tract infection / Cystitis / Pyelonephritis 8/8 Excellent Good / patients Efficacy mg / / / / / / / / / / 9. Daily dose mg 9/9 / / / / / / / /. mg / / / / / / / Table. Overall clinical efficacy of DRPM in complicated UTI at end of treatment Pyuria Bacteriuria Eliminated Decreased Replaced Unchanged Effect on pyuria Excellent Moderate Poor Cleared Decreased.%.%.9% Unchanged.% Effect on bacteriuria 8 8. % % 9. %. % patients Overall effectiveness / 9.8% mg Table
Table 8. Correlation between isolated organism and clinical response Isolated organism patients Clinical efficacy Excellent Good Fair Poor Efficacy Monomicrobial infection Gram-positive bacteria Gram-negative bacteria Staphylococcus aureus Staphylococcus epidermidis Streptpcoccus pneumoniae Enterococcus faecalis Subtotal Branhamella catarrhalis Escherichia coli Klebsiella pneumoniae Enterobacter cloacae Proteus mirabilis Morganella morganii Pseudomonas aeruginosa Pseudomonas sp. Haemophilus influenzae Pasturella multocida 9 Subtotal 8. Polymicrobial infection. 9 9. Efficacy: Excellent Good / patients Table 9. Correlation between infection and bacteriological response Chronic respiratory tract infection a Disease group Bacterial effects Eradication patients Eliminated Decreased Replaced Unchanged 8. Complicated urinary tract infection b 9. 8 9.9 Eradication: Eliminated Replaced / patients Bacterial effects of complicated UTI diverted results of bacteriuria eliminated, decreased, replaced, unchanged. a,,, Pulmonary emphysema with infection b Cystitis, Pyelonephritis.8 Table GPT GOT mg. mg. Table GPT.. 9 ALP. 9 GOT.8 Table 98.
Doripenem II Table. Correlation between isolated organism and bacteriological response Isolated organism patients Eliminated Bacterial effects Decreased Replaced Unchanged Eradication Monomicrobial infection Gram-positive bacteria Gram-negative bacteria Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Enterococcus faecalis Subtotal Branhamella catarrhalis Escherichia coli Klebsiella pneumoniae Enterobacter cloacae Proteus mirabilis Morganella morganii Pseudomonas aeruginosa Pseudomonas sp. Haemophilus influenzae Pasturella multocida 9 8 Subtotal 9. Polymicrobial infection 9. 8 9.9 Eradication: Eliminated Replaced / patients Table. Eradication of isolated organism Isolated organism bacterial strains Bacterial efficacy Eliminated Persisted Eradication Gram-positive bacteria Staphylococcus aureus Staphylococcus epidermidis Coagulase negative Staphylococcus Streptococcus pneumoniae Streptococcus agalactiae Streptococcus constellatus Enterococcus faecalis Subtotal 9. Gram-negative bacteria Branhamella catarrhalis Escherichia coli Citrobacter freundii Klebsiella pneumoniae Enterobacter cloacae Proteus spp. Morganella morganii Pseudomonas aeruginosa Haemophilus influenzae other gram-negative rods 9 Subtotal 9 9.9 8 9 9. Table mg. Table Table mg
Table. Isolated organisms after DRPM treatment Isolated organism Staphylococcus aureus -Streptococcus -non-streptococcus Enterococcus faecalis Enterococcus faecium Pseudomonas aeruginosa Flavobacterium sp. Stenotrophomonas maltophilia Fungi patients with organisms/ observed patients bacterial strains 9 /.% Table. Correlation between daily dose and adverse drug reaction symptoms Adverse drug reaction Daily dose symptom patients mg mg mg mg observed patients patients seen Appearance Eruption Tongue numbness Headache.8..8.. Table. Correlation between daily dose and adverse drug reaction abnormal laboratory findings Adverse drug reaction Daily dose laboratory data patients mg mg mg mg observed patients patients seen Appearance.8.... Table. Correlation between daily dose and adverse drug reaction abnormal laboratory findings by test item Adverse drug reaction laboratory findings mg Daily dose mg mg mg event observed patients Incidence Basophilia Eosinophilia Neutropenia Neutropenia Segmented Thrombocytosis GOT increased GPT increased ALP increased LDH increased -GTP increased LAP increased Serum potassium increased 8 9 9 9 9 8 9 9...9..9.8......
Doripenem II Table. Correlation between diagnosis and DRPM safety profile patients Safe Safety evaluation Nearly safe Slightly uneasy Uneasy Safety Respiratory infection 98.. 9. Secondary infection of chronic respiratory disease 9.. Diffuse panbronchiolitis Pneumonia Urinary tract infection 98. Complicated urinary tract infection Cystitis Pyelonephritis 9 9 8 98.. 9. Prostatitis 9 98. Safety: Safe Nearly safe / patients Table. Correlation between daily dose and DRPM safety profile Respiratory infection Secondary infection of chronic respiratory disease Diffuse panbronchiolitis Pneumonia Urinary tract infection Complicated urinary tract infection Cystitis Pyelonephritis Prostatitis Safe Nearly safe / patients Safety mg / / / / / / / /. mg / / / / / / / / / / / / / / / 9.8 Daily dose mg / / / / / / / / / / / /. mg / / / / / / / / / /.. Table 9 mg.. µ g g..9 Table Fig. III DHP-I P. aeruginosa DRPM II
Table. Correlation between diagnosis and DRPM usefulness patients Extremely useful Usefulness Slightly Useful useful Not useful Usefulness Respiratory tract infection 9.9. 9 8. Secondary infection of chronic respiratory disease 8 9. Complicated urinary tract infection Cystitis Pyelonephritis 8 9.9. 8. 9 9. Usefulness: Extremely useful Useful / patients Table 9. Correlation between daily dose and DRPM usefulness mg Respiratory tract infection / / Secondary infection of chronic respiratory disease / / Complicated urinary tract infection / Cystitis / Pyelonephritis 8/8 Extremely useful Useful / patients Usefulness mg 9/ / / / / / / / / / 88.9 Daily dose mg 9/9 / / / / / / / /. mg / / / / / / / 8/8 Table. Pharmacokinetic profiles in determining DRPM sputum level DRPM: mg, Infusion time: minutes Subject No. AUC a g h/ml CL b L/h T/ c h Cmaxserum d g/ml Cmaxsputum e g/g Cmax Ratio f.9.9.9.... 9. 9.8..9..... 8.. 8..9.........9. Mean SD...8.8........ a AUC: calculated by trapezoidal method b CL clearance : calculated by dose/auc c T/ : half-life at phase d Cmaxserum: observed values at h e Cmaxsputum: obtained from observation f Cmax Ratio: Cmaxsputum/Cmaxserum
Doripenem II Serum concn g/ml or Sputum concn g/g.. 8 Time h mean serum concentration mean sputum concentration Fig.. DRPM concentration in serum and sputum DRPM: mg, Infusion time: minutes. 9. 9. II.8.8 GPT. 98. mg. 9. I mg mg mg mg DRPM Doripenem in vitro Suppl :, β doripenem Suppl :, Doripenem dehydropeptidase-i Suppl :9 9, Doripenem I Suppl :, UTI UTI Chemotherapy : 8, 98 Chemotherapy 9: 8 89, 99
Early phase II study of doripenem, a new carbapenem antibiotic for injection Jingoro Shimada, Keizo Yamaguchi, Kohya Shiba, Atsushi Saito, Sadao Kamidono and Takeshi Inamatsu Institute of Medical Science, St. Marianna University School of Medicine, Sugao Miyamae-ku, Kawasaki, Kanagawa, Japan Department of Microbiology, Toho University School of Medicine Department of Department of Infection Control, Jikei University Faculty of Medicine, University of the Ryukyus Kobe University, School of Medicine Tokyo Metropolitan Geriatric Medical Center A multicenter prospective early phase II study was conducted at sites in Japan in patients with internal and urologic infection to evaluate the dosage and administration of doripenem DRPM, a new carbapenem antibiotic for injection, and to assess its safety and efficacy. Subjects numbered, of whom internal medicine:, urology: were evaluated for efficacy, for safety in abnormal laboratory test findings, and in abnormal symptoms. The usefulness of DRPM in was evaluated and DRPM concentration in the sputum determined in. DRPM was administered intravenously for to minutes at mg b. i. d., mg b. i. d., mg t. i. d., and mg b. i. d., with the following results: Efficacy was 9. 9 in internal medicine patients and 9. in urology patients, for an overall efficacy of 9.. Bacterial eradication was 8. 9 in internal medicine patients and 9. in urology patients, for an overall bacterial eradication of 9.9. In safety, adverse drug reactions symptoms observed in patients events: tongue numbness, headache, and rash were not serious and disappeared after completion of treatment. Adverse drug reactions abnormal laboratory test findings observed in patients events included increased GPT cases,got cases, and eosinophilia cases, all of which were slight and improved or returned to normal after completion of treatment. Overall safety was 98.. Of the patients evaluated for DRPM usefulness, usefulness rate 9.9 9 in internal medicine patients and 9.9 in urology patients, for an overall usefulness of 9.. These results show that DRPM has the expected efficacy without adverse drug reactions that might raise clinical issues, so DRPM is expected to produce sufficient therapeutic effect in treating target infection.