Sweden has been increasingly affected by drug shortage and the public healthcare system has identified a large amount of antibiotics risking shortage. Drug shortage of antibiotics is a worldwide problem with complex causes and consequences affecting many countries healthcare systems. The aim of this study is to investigate the shortage of cefadroxil and meropenem. More specifically, to investigate risk factors in the supply chain contributing to their backorders as well as possible consequences for Swedish healthcare due to shortage.  To formulate the supply chain for cefadroxil and meropenem, the active pharmaceutical ingredient (API) manufacturers, final dosage form (FDF) holders and market authorization holders (MAHs)were identified. 4 active API manufactures, 18 active FDF holders and 4 MAHs were identified for cefadroxil and 4 active API manufactures, 32 FDF holders and 8 MAHs were identified for meropenem. In order to analyse the causes behind these antibiotic shortages, problems with the manufactures were researched using various sources. Since API production is the first step in thesupply chain, problems connected to the API manufactures was the sole focus in this study. Research identified several problems with the API manufacturers for both antibiotics, indicating that the shortages can in fact be explained by issues in the supply chain.  In order to calculate and get an estimate of the health economic costs for society, a model based on direct and indirect costs was used. The direct costs were calculated by comparing the most suitable alternative treatment methods. For cefadroxil there were 5 alternatives in the case of shortage for the oral suspension from Mylan AB (the only product covered in this section of the report due to limited data), whereof 3 of the alternatives still were cefadroxil products. These 3 were cefadroxil dispersible tablets, cefadroxil capsules and Grüncef. The other 2 alternatives were Clindamycin and the combination antibiotic Trimethoprim/Sulfamethoxazol (Eusaprim R). Meropenem had only one identified alternative drug called imipenem. In addition to comparing alternative treatments, the cost of extra labor hours spent on dealing with shortages as well as the increased risk of AMR was also also investigated closely. The indirect costs were based on loss of production due to patient care being longer and more demanding as a result of unforeseen side effects caused by the alternative treatments. This was analyzed qualitatively, in other words no definitive cost was calculatedfor loss of production. Results showed that the exchange from Cefadroxil Mylan oral suspension to cefadroxil dispersible tablets would cost Sweden approximately +35 105 SEK/day. The exchange to cefadroxil capsules would cost -30 939 SEK/day and for Grüncef the cost would be +311 814 SEK/day. As for the other 2 antibiotics, the cost would be -23 103 SEK/day for Clindamycin and -53 084 SEK/day for Eusaprim R. When exchanging meropenem for imipenem, the direct cost was estimated to +343 299 SEK/day. Regarding the cost for extra labor hours spent on dealing with shortage, this was estimated to 1.6 MSEK per shortage, regardless of the antibiotic and shortage duration. The costscalculated for the replacement pharmaceuticals were based on worst case scenarios for when all MAHs had their products unavailable. If the calculated values are of any relevance for real life situations depends on the fragility of the supply chain. In other words, how big these health economicconsequences are for Swedish healthcare is dependant on the risk of unavailability for these antibiotics which goes back to the fragility of the supply chain. In regards to AMR, research showed that substituting cefadroxil for clindamycin and meropenem for imipenem increased the risk of AMR and as a consequence, the direct cost increased as well. The use of clindamycin to treat infections caused by Methicillin-Resistant Staphylococcus Aureus (MRSA) could lead to an additional cost of +3665 SEK/outpatient visit in the case of induced resistance against the antibiotic. Substituting meropenem for imipenem would result in an additional cost of +1160 SEK/day assuming that the bacteria behind the infection is ESBLcarba, an Enterobacteriaeac able to break down carbapenems (a class of antibiotics in which meropenem and imipenem reside). Using licensed drugs could minimize this risk but would however come at a cost for the patients health due to the extended lead time as a result of importation. This would in turn increase the indirect cost to society in the form of loss of production. Despite maybe lowering the risk of AMR, the calculated costs for shortage/day show that using licensed drugs would in fact increase the direct cost a great deal. The calculations for Grüncef and imipenem illustrate this as they proved to be much more costly than the other alternative treatments.

Os estudos de bioequivalência são realizados em humanos, por meio da administração dos medicamentos em estudo pela mesma via extravascular, sob condições experimentais padronizadas, seguida pela determinação das concentrações plasmáticas do fármaco em função do tempo. Nestes estudos considera-se que curvas estatisticamente semelhantes de decaimento sanguíneo de fármacos produzem o mesmo resultado em termos de eficácia e segurança. A partir das curvas de concentração em função do tempo obtidas, determinam-se os parâmetros farmacocinéticos Cmax, tmax e ASC. A bioequivalência entre dois produtos é estabelecida por meio do IC 90%, que deve estar entre 80 a 125% para os parâmetros farmacocinéticos Cmax e ASC. O cronograma de coleta de amostras biológicas é um dos aspectos mais críticos no planejamento de estudos de bioequivalência, pois este afeta diretamente a determinação dos parâmetros farmacocinéticos utilizados na avaliação da bioequivalência. Outro aspecto importante relacionado a este tipo de estudo é a diferença de teor entre os produtos a serem submetidos ao estudo de bioequivalência, que segundo a legislação brasileira vigente, deve ser menor ou igual a 5%. Neste trabalho foram avaliados diferentes cronogramas de coleta de amostras sangue, avaliando-se o impacto destes no resultado final de um estudo de bioequivalência e, além disso, a influência da diferença de teor de fármaco entre dois produtos que levaria à bioinequivalência também foi investigada. Para tanto simulações matemáticas e um estudo in vivo foram conduzidos. O fármaco modelo escolhido foi a cefadroxila, por apresentar características farmacocinéticas e farmacodinâmicas ideais. O programa Microsoft Office Excel 2003 foi utilizado para simular as concentrações plasmáticas e determinar o IC 90%. As simulações foram feitas por meio de dois modelos: modelo baseado em máximos e mínimos de parâmetros farmacocinéticos, e modelo baseado em coeficientes de variação intra e inter-individuais do fármaco. Dez diferentes doses, entre -10% a 20% da dose referência, e 6 cronogramas de coleta foram avaliados. O estudo in vivo foi realizado com quatro doses diferentes de cefadroxila. A bioequivalência entre as doses e em diferentes cronogramas de coleta foi avaliada em 24 voluntários sadios do sexo masculino. Os voluntários receberam as quatro doses do estudo em desenho cruzado, em quatro períodos e quatro seqüências, com washout de 7 dias entre as doses. As concentrações plasmáticas de cefadroxila, até 8 horas após a administração, foram determinadas por cromatografia líquida de alta eficiência com detecção DAD. Os parâmetros farmacocinéticos tmax, Cmax e AUC0-t foram determinados nas diferentes doses e cronogramas de coleta, sendo que o critério para estabelecer-se a bioequivalência foi baseada nos resultados do IC 90% dos parâmetros farmacocinéticos Cmax e AUC0-t. Os resultados obtidos nas simulações mostraram boa correlação com os dados reais obtidos a partir de estudos in vivo. As simulações baseadas em coeficientes de variação intra e inter-individuais descreveram melhor os resultados observados no estudo in vivo. De acordo com os resultados obtidos no estudo in vivo pode-se concluir que cronogramas de coletas com menos amostras são tão eficientes quanto cronogramas de coletas com mais amostras, desde que o tempo de tmax esteja incluído. Em relação ao teor de fármaco, concluiu-se que dois produtos com diferença de teor menor ou igual a 11% ainda são bioequivalentes e que diferença maior ou igual a 14% resultam em bioinequivalência. Observou-se ainda que o parâmetro farmacocinético ASC0-t é mais sensível que Cmax para detectar diferenças. / Bioequivalence studies are designed to compare the in vivo performance of different formulations of the same drug or different drug products by a randomized crossover study. Pharmacokinetic parameters are obtained from the drug concentration-time profile in blood, serum, or plasma. The most frequently used pharmacokinetic parameters are area under the plasma or blood concentration-time curve (AUC), maximum concentration (Cmax) and time to achieve maximum concentration (tmax). Bioequivalence is concluded if the average bioavailability of the test formulation is within (80%, 125%) that of the reference formulation, with a certain assurance, that is, an equivalence criterion of 80% to 125% for assessment of bioequivalence based on the ratio of average bioavailability is employed. The logarithmic transformation is used for AUC and Cmax. Accuracy in measuring pharmacokinetics parameters directly affects accuracy of bioequivalence tests. Since the number of blood samples per patient is limited, sampling points should be chosen such that the time concentration profile is adequately defined so as to allow the calculation of relevant parameters. According to guidelines proposed by the National Agency of Sanitary Vigilance of Brazil (ANVISA), bioequivalence studies can be conducted only if the difference in drug content between the reference and test product is less than or equal to 5%. The goals of this study are to evaluate the influence of differences in amount of active moiety present in the formulation and possibility of reducing the number of sampling points in bioequivalence studies and to discuss the impact of these parameters in bioequivalence conclusions. For these approaches, simulations and an in vivo study were done. The drug selected was cefadroxil. Cefadroxil presents ideal pharmacokinetics and pharmacodynamics characteristics for this kind of study, such as high bioavailability, low intra and intersubject variability, short elimination rate and wide therapeutic range. Microsoft Office Excel 2003 software was used to simulate drug concentration-time profiles for different doses and several sampling schedules, and to determine 90% confidence interval. Simulations were done by two models: a) based on assumed maximum and minimum pharmacokinetic parameters values; b) based on assumed intra and intersubject variability. Ten different doses, ranging from -10% to 20% of the reference dose, and six sampling schedules were evaluated. The in vivo study was performed with four different cefadroxil doses. Their relative bioavailability were evaluated in 24 healthy volunteers who received a single oral dose of each preparation. An open, randomized clinical trial designed as four-periods and four sequences crossover with 7-days washout between doses was employed. Plasma samples for assessments of their cefadroxil concentration by HPLC-DAD were obtained over 8 h after administration. Pharmacokinetics parameters tmax, Cmax and AUC0-t were evaluated using different doses and sampling schedules. For the purpose of bioequivalence analysis Cmax and AUC0-t were considered. For each schedule, to claim bioequivalence in average bioavailability, a 90% confidence interval was constructed for ratio of average between test and reference products and compared with (80%, 125%) limits. If the constructed confidence interval falls within the limits, then the two formulations are considered bioequivalent. The results obtained by simulate time-concentration profiles, showed good correlation with real data. Comparing the results obtained through in vivo study and the two simulations models, the simulations based in intra and intersubject variability was more predictive. In conclusion, no significant differences were found between sampling schedules evaluated, since the sampling time around tmax were maintained in sampling schedules. Bioinequivalence was observed when the difference between cefadroxil doses was higher than 14%. The parameter AUC0-t was more sensitive than Cmax to detect differences.

Os estudos de bioequivalência são realizados em humanos, por meio da administração dos medicamentos em estudo pela mesma via extravascular, sob condições experimentais padronizadas, seguida pela determinação das concentrações plasmáticas do fármaco em função do tempo. Nestes estudos considera-se que curvas estatisticamente semelhantes de decaimento sanguíneo de fármacos produzem o mesmo resultado em termos de eficácia e segurança. A partir das curvas de concentração em função do tempo obtidas, determinam-se os parâmetros farmacocinéticos Cmax, tmax e ASC. A bioequivalência entre dois produtos é estabelecida por meio do IC 90%, que deve estar entre 80 a 125% para os parâmetros farmacocinéticos Cmax e ASC. O cronograma de coleta de amostras biológicas é um dos aspectos mais críticos no planejamento de estudos de bioequivalência, pois este afeta diretamente a determinação dos parâmetros farmacocinéticos utilizados na avaliação da bioequivalência. Outro aspecto importante relacionado a este tipo de estudo é a diferença de teor entre os produtos a serem submetidos ao estudo de bioequivalência, que segundo a legislação brasileira vigente, deve ser menor ou igual a 5%. Neste trabalho foram avaliados diferentes cronogramas de coleta de amostras sangue, avaliando-se o impacto destes no resultado final de um estudo de bioequivalência e, além disso, a influência da diferença de teor de fármaco entre dois produtos que levaria à bioinequivalência também foi investigada. Para tanto simulações matemáticas e um estudo in vivo foram conduzidos. O fármaco modelo escolhido foi a cefadroxila, por apresentar características farmacocinéticas e farmacodinâmicas ideais. O programa Microsoft Office Excel 2003 foi utilizado para simular as concentrações plasmáticas e determinar o IC 90%. As simulações foram feitas por meio de dois modelos: modelo baseado em máximos e mínimos de parâmetros farmacocinéticos, e modelo baseado em coeficientes de variação intra e inter-individuais do fármaco. Dez diferentes doses, entre -10% a 20% da dose referência, e 6 cronogramas de coleta foram avaliados. O estudo in vivo foi realizado com quatro doses diferentes de cefadroxila. A bioequivalência entre as doses e em diferentes cronogramas de coleta foi avaliada em 24 voluntários sadios do sexo masculino. Os voluntários receberam as quatro doses do estudo em desenho cruzado, em quatro períodos e quatro seqüências, com washout de 7 dias entre as doses. As concentrações plasmáticas de cefadroxila, até 8 horas após a administração, foram determinadas por cromatografia líquida de alta eficiência com detecção DAD. Os parâmetros farmacocinéticos tmax, Cmax e AUC0-t foram determinados nas diferentes doses e cronogramas de coleta, sendo que o critério para estabelecer-se a bioequivalência foi baseada nos resultados do IC 90% dos parâmetros farmacocinéticos Cmax e AUC0-t. Os resultados obtidos nas simulações mostraram boa correlação com os dados reais obtidos a partir de estudos in vivo. As simulações baseadas em coeficientes de variação intra e inter-individuais descreveram melhor os resultados observados no estudo in vivo. De acordo com os resultados obtidos no estudo in vivo pode-se concluir que cronogramas de coletas com menos amostras são tão eficientes quanto cronogramas de coletas com mais amostras, desde que o tempo de tmax esteja incluído. Em relação ao teor de fármaco, concluiu-se que dois produtos com diferença de teor menor ou igual a 11% ainda são bioequivalentes e que diferença maior ou igual a 14% resultam em bioinequivalência. Observou-se ainda que o parâmetro farmacocinético ASC0-t é mais sensível que Cmax para detectar diferenças. / Bioequivalence studies are designed to compare the in vivo performance of different formulations of the same drug or different drug products by a randomized crossover study. Pharmacokinetic parameters are obtained from the drug concentration-time profile in blood, serum, or plasma. The most frequently used pharmacokinetic parameters are area under the plasma or blood concentration-time curve (AUC), maximum concentration (Cmax) and time to achieve maximum concentration (tmax). Bioequivalence is concluded if the average bioavailability of the test formulation is within (80%, 125%) that of the reference formulation, with a certain assurance, that is, an equivalence criterion of 80% to 125% for assessment of bioequivalence based on the ratio of average bioavailability is employed. The logarithmic transformation is used for AUC and Cmax. Accuracy in measuring pharmacokinetics parameters directly affects accuracy of bioequivalence tests. Since the number of blood samples per patient is limited, sampling points should be chosen such that the time concentration profile is adequately defined so as to allow the calculation of relevant parameters. According to guidelines proposed by the National Agency of Sanitary Vigilance of Brazil (ANVISA), bioequivalence studies can be conducted only if the difference in drug content between the reference and test product is less than or equal to 5%. The goals of this study are to evaluate the influence of differences in amount of active moiety present in the formulation and possibility of reducing the number of sampling points in bioequivalence studies and to discuss the impact of these parameters in bioequivalence conclusions. For these approaches, simulations and an in vivo study were done. The drug selected was cefadroxil. Cefadroxil presents ideal pharmacokinetics and pharmacodynamics characteristics for this kind of study, such as high bioavailability, low intra and intersubject variability, short elimination rate and wide therapeutic range. Microsoft Office Excel 2003 software was used to simulate drug concentration-time profiles for different doses and several sampling schedules, and to determine 90% confidence interval. Simulations were done by two models: a) based on assumed maximum and minimum pharmacokinetic parameters values; b) based on assumed intra and intersubject variability. Ten different doses, ranging from -10% to 20% of the reference dose, and six sampling schedules were evaluated. The in vivo study was performed with four different cefadroxil doses. Their relative bioavailability were evaluated in 24 healthy volunteers who received a single oral dose of each preparation. An open, randomized clinical trial designed as four-periods and four sequences crossover with 7-days washout between doses was employed. Plasma samples for assessments of their cefadroxil concentration by HPLC-DAD were obtained over 8 h after administration. Pharmacokinetics parameters tmax, Cmax and AUC0-t were evaluated using different doses and sampling schedules. For the purpose of bioequivalence analysis Cmax and AUC0-t were considered. For each schedule, to claim bioequivalence in average bioavailability, a 90% confidence interval was constructed for ratio of average between test and reference products and compared with (80%, 125%) limits. If the constructed confidence interval falls within the limits, then the two formulations are considered bioequivalent. The results obtained by simulate time-concentration profiles, showed good correlation with real data. Comparing the results obtained through in vivo study and the two simulations models, the simulations based in intra and intersubject variability was more predictive. In conclusion, no significant differences were found between sampling schedules evaluated, since the sampling time around tmax were maintained in sampling schedules. Bioinequivalence was observed when the difference between cefadroxil doses was higher than 14%. The parameter AUC0-t was more sensitive than Cmax to detect differences.